PHARMACOKINETICS

FOR SECOND YEAR STUDENTS

CLINICAL PHARMACY DEPARTMENT

2019/ 2020
 Dr: Abla Mohamed Ebeid
Clinical Pharmacy Department
Define PK

Importance of PK

ADME processes

Plasma concentration curve

Methods of drug absorption

2
 Definition :
the study of the rates of the transfer process associated with
drug absorption, distribution, metabolism, and excretion
(What the body do to the drug).

Pharmacokinetics (PK) involves four main process (ADME):

absorption, distribution, metabolism, and excretion

3
 Pharmacokinetics

Drug in GIT
Absorpti
on
Drug in blood

Distribution
Drug in tissues
Drug metabolites Drug in urine/bile

Drug at receptor
Pharmacodynamics

Desired response No response Unwanted response

4
Pharmacodynamics refers to the relationship between the
drug at the site of action (receptor) and pharmacologic
response

How the drug affect the body

5
The phenomena where the concentration of a drug is
greatly reduced before it reaches the circulatory system
reducing drug bioavailability.

The liver metabolizes many drugs, sometimes to such an

extent that only a small amount of active drug reaches
the rest of the circulatory system from the liver.

Sublingual route shows no first pass effects

7
8
This refers to the circulation of drugs from the liver to
the bile, then to the small intestine, followed by
reabsorption again through the enterocyte (often by the
bacterial help) and transport back to circulation and liver.
Drugs may be toxic as they reach unexpectedly high
concentrations.
Enterohepatic circulation increase plasma
concentration of drugs like oral contraceptive, estrogen

9
10
 Also called multidrug resistance protein 1 (MDR1)
An important efflux protein of the cell membrane that pumps
many foreign substances out of cells.
Found in:
intestinal epithelium (decrease drug bioavailability)
liver cells (remove drug in bile)
proximal tubule of the kidney (remove drug in urine)
endothelial cells composing the blood–brain barrier
(preventing entry to the brain)
Some cancer cells (preventing drug entry causing cancer
multi-drug resistant).

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12
13
After absorption to blood stream, drug is rapidly
distributed into the interstitial and intercellular fluids

Liver, kidney, brain, and other well-perfused organs

receive most of the drugs

14
Plasma proteins bound to many drugs. This bounded
drugs have no action at receptor site and only
unbounded fraction has a pharmacological action

Displacement of highly bounded drug from plasma

protein by other drugs can affect the pharmacological
action greatly ex: warfarin

Drug distribution determine the model of drug

kinetics (one compartment or two compartment)

15
16
Metabolism of drug occur mainly in the liver

Metabolism involve two main process

1-phase 1 oxidation reaction
2-phase 2( conjugation) reaction

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18
Excretion is the irreversible removal of drug from
the body and commonly occurs via the kidney or
biliary tract.
Kidney is the main organ for excretion of drugs and
their metabolites

elimination from lung is important mainly for the

elimination of anesthetic drugs through sweating

19
is the discipline that applies pharmacokinetic concepts
and principles in humans in order to design
individualized dosage regimens which optimize the
therapeutic response of a medication while
minimizing the chance of an adverse drug reaction.

20
Receptor sites of drugs are generally inaccessible to our
observations or are widely distributed in the body, and
therefore direct measurement of drug concentrations at
these sites is not practical.
we cannot directly sample drug concentration in this tissue.
However, we can measure drug concentration in the blood
or plasma, urine, saliva, and other easily sampled fluids.

21
Differences in an individual's ability to metabolize and
eliminate the drug (e.g., genetics)

Variations in drug absorption

Disease states or physiologic states (e.g., extremes of

age) that alter drug absorption, distribution, or
elimination

Drug interactions

22
is the study of the sources of variability in the drug
pharmacokinetic behavior among individuals who are the
target patient population.

The effect of each factor on the drug pharmacokinetic

behavior can be quantified and used in recommendations
for the proper use of the drug in the different patient
subpopulations.

This is because in the presence of high variability in the

drug pharmacokinetics, the same dose of the drug can
produce a wide range of concentrations in different patients.
These concentrations can be high (toxic), average
(therapeutic), or low (sub therapeutic).
23
It is the field of science that applies the pharmacokinetic
principles to determine the relationship between the
systemic exposure of a compound and its toxicity.

Toxic kinetic studies are pharmacokinetic studies

perduring formed to determine the absorption,
distribution, metabolism, and elimination of the drug or
chemicals the toxicity studies.

The information obtained from these toxic kinetic

studies in laboratory animals is extrapolated to establish
the drug concentration-toxic effect relationship in humans.

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1. Design and Evaluation of Dosage Forms
2. Evaluation of Drug Formulation
3. Pharmacological Testing
4. Toxicological Testing
5. Evaluation of Organ Function
6. Dosing Regimen Design

25
is defined as the use of assay procedures for
determination of drug concentrations in plasma, and
the interpretation and application of the resulting
concentration data to develop safe and effective drug
regimens.

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If performed properly, this process allows for the
achievement of therapeutic concentrations of a drug
more rapidly and safely than can be attained with
empiric dose changes.

Together with observations of the drug's clinical

effects, it should provide the safest approach to optimal
drug therapy.

27
is defined as the use of assay procedures for determination
of drug concentrations in plasma, and the interpretation and
application of the resulting concentration data to develop
safe and effective drug regimens.

If performed properly, this process allows for the

achievement of therapeutic concentrations of a drug
more rapidly and safely than can be attained with empiric
dose changes.

Together with observations of the drug's clinical effects, it

should provide the safest approach to optimal drug
therapy.

28
1. Some drug have narrow therapeutic window (NTW)

2. Individual variations “Patients usually do not

response in a similar way when they are placed on
identical dosage regimen”.

3. Some may demonstrate adequate response, others

may demonstrate toxicity, and other may not be
affected at all by the drug.

4. So, make therapeutic drug monitoring to these drug

for each patients.
29
1.A good correlation exists between the pharmacologic response
and plasma concentration.

2.Wide inter subject variation in plasma drug concentrations

results from a given dose.

3.The drug has a narrow therapeutic index (i.e., the therapeutic

concentration is close to the toxic concentration).

4.The drug's desired pharmacologic effects cannot be assessed

readily by other simple means (e.g., blood pressure measurement
for antihypertensive).
30
1.There is no well-defined therapeutic plasma
concentration range.

2.The formation of pharmacologically active metabolites

of a drug complicates the application of plasma drug
concentration data to clinical effect unless metabolite
concentrations are also considered.

3.There are no significant consequences associated with

too high or too low levels.

31
 Plasma concentration is the simplest widely used
method to evaluate the therapeutic and toxic effect of
the drug.
The changes in drug concentration are as following:
A- An increase in the amount of drug in the body
(absorption)
B- A decrease in the amount of drug in the body
(metabolism and excretion)
C- No change in the amount of drugs in the body
(distribution)

32
33
Some drugs are administered IV, so these agents have
no absorptive phase associated with their
pharmacokinetic profile.

IV administration of drugs is followed by distribution

and elimination, and thus the time-amount profile of
the drug in the body is a decreasing function as shown
below.

The time-amount profile of the drug in the body is a

decreasing function

34
1-Concentration response plot: increase concentration
increase response till reaching maximal response (
Most drugs)

35
 The response not related to the dose, the cause may be:
a- counterclockwise hysteresis due to increased sensitivity
or formation of active metabolite

36
37
• Three new drug for treating diabetes were
introduced in the market. The following table represent
the relation between the plasma concentration and the
drug effects as indicated by the decrease in blood glucose
level
• For each drug determine the pharmacokinetic and
pharmacodynamics interface after plotting the
concentration effect graph

38
39
 Rate:The velocity with which a reaction or a process occurs
is called as its rate.

Order of reaction: The manner in which the concentration

of drug (or reactants) influences the rate of reaction or process is
called as the order of reaction or order of process.
Consider the following chemical reaction:

Drug A Drug B

The rate of forward reaction is expressed as: -dA/dt

Negative sign indicates that the concentration of drug A
decreases with time t.

40
The rate of forward reaction is expressed as: -dA/dt
Negative sign indicates that the concentration of drug A
decreases with time t. As the reaction proceeds, the
concentration of drug B increases and the rate of
reaction can also be expressed as: dB/dt
dC/dt = -KCn
rate constant = K
order of reaction = n

41
 If n = 0, equation becomes:
dC/dt = -Ko where

Ko = zero-order rate constant (in mg/min)

Zero-order process can be defined as the one whose rate is

independent of the concentration of drug undergoing
reaction i.e. the rate of reaction cannot be increased further by
increasing the concentration of reactants. Finally
C = Co – Ko t

42
Zero-order process can be defined as the one whose
rate is independent of the concentration of drug
undergoing reaction i.e. the rate of reaction cannot
be increased further by increasing the concentration
of reactants. Finally
C = Co – Kot

43
If a graph constructed by plotting the concentration of
drug versus time, it will yield a straight line.

The zero-order rate constant k0 may be obtained from

the slope of the line, and the y intercept will be Co

44
45
Half-life (t½) or half-time is defined as the time
period required for the concentration of drug to
decrease by one-half.
t1/2 = Co / 2 Ko
Half-life (t½) is dependent on drug concentration.

46
1. Metabolism/protein-drug binding/enzyme or carrier-
mediated transport under saturated conditions. The rate
of metabolism, binding or transport of drug remains
constant as long as its concentration is in excess of
saturating concentration.

2. Administration of a drug as a constant rate intravenous

(i.V.) infusion.

3. Controlled drug delivery such as that from

intramuscular (I.M.) implants or osmotic pumps.

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Example: The administration of a 1000 mg of drug X
resulted in the following concentrations:
Time Conc. (mg/L)

0 100

4 90

6 85

10 75

12 70

Zero-Order Reactions: example

What is the order of the elimination process (zero or first)?
What is the rate constant?
48
Since the decline in drug conc. displayed a linear
decline on normal scale, drug X has a zero order
decline.
The zero-order rate constant k0 may be obtained from
the slope of the line, and the y intercept will be Ao

49
 From the equation displayed on the figure (intercept =
100, slope = -2.5)
Slope = (y2-y1)/(x2-x1)
The elimination rate constant is 2.5 mg/hr

50
If n = 1, equation becomes:
dC/dt = - K Cn
where K = first-order rate constant (in
time-1or per hour)

51
By integration:
C = C o – e –Kt
ln C = ln Co - K t
N.B.: 2.303 log N = ln N
log C = log Co – Kt /2.303
The first-order process is also called as
monoexponential rate process. Thus, a first-order
process is characterized by logarithmic or exponential
kinetics i.e. a constant fraction of drug undergoes
reaction per unit time.

52
Slope = t1/2 = ln 2/K
t1/2 = 0.693 / K

. 53
From equation shows that, in contrast to zero-order
process, the half-life of a first-order process is a
constant and independent of initial drug
concentration i.e. irrespective of what the initial drug
concentration is, the time required for the concentration
to decrease by one-half remains the same.
Most pharmacokinetic processes including
absorption, distribution and *elimination follow
first-order kinetics.

54
 First order Zero order
Elimination rate depend on the amount of the drug Elimination rate is constant
dA/dt =-KA (dA/dt) = -K0
Elimination rate constant K (Constant) Elimination rate constant K0 (Constant)
Depend on the amount of the drug remaining Doesn’t depend on the amount of the drug
dA/dt = -KA dA/dt = -K
Ln A = ln Ao – Kt A= Ao-Kt
- Curved line on the rectangular coordinate Linear line on the rectangular coordinate graph
graph paper paper
Linear line on semi log paper -
T 1/2 = ln 2/K = 0.693/K T 1/2 = 0.5 Ao/K
Constant Depends on the amount remaining
K hr-1 K (mg/hr)
Intercept: Log Ao Intercept: Ao
K0 & k is constant in zero and 1st order for the
same drug and the same patient

55
the drug distributes instantaneously and
homogenously throughout the compartment. Drug
elimination also occurs from the compartment
immediately after injection. 56
The one-compartment open model offers the simplest
way to describe the process of drug distribution and
elimination in the body. This model assumes that the
drug can enter or leave the body (ie, the model is
"open"), and the body acts like a single, uniform
compartment.

The simplest route of drug administration from a

modeling perspective is a rapid intravenous injection
(IV bolus).

57
1. Apparent Volume of Distribution (Vd)
2. Elimination rate constant (K)
3. Elimination half life (t1/2)
4. Clearance (Cl)

Vd= 10 L
Vd= 100 L

58
is a hypothetical volume that relates drug serum
concentrations to the amount of drug in the body.
Thus, the dimension of volume of distribution is in
volume units, such as L or mL.
At any given time after drug has been absorbed from
extravascular sites and the serum and tissue drug
concentrations are in equilibrium, the serum
concentration for a drug (C) is equal to the quotient of
the amount of drug in the body (A) and the volume of
distribution: C = A/Vd

59
The volume of distribution can be: very small if the drug
is primarily contained in the blood (warfarin V = 5–7 L),
or very large if the drug distributes widely in the body and
is mostly bound to bodily tissues (digoxin V = 500 L).
Volume of distribution is an important pharmacokinetic
parameter because it determines the loading dose (LD) that
is required to achieve a particular steady-state drug
concentration immediately after the dose is administered:

LD = Css Vd
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- Lipid solubility of drug
- Degree of plasma protein binding
- Affinity for different tissue proteins
- Fat : lean body mass
- Disease like Congestive Heart Failure (CHF),
uremia, cirrhosis

61
 Demographic data of patient
age, weight, gender, etc.

Medical condition
renal failure, liver failure, heart failure, etc.
NB :
most patients will not actually attain steady state after a
loading dose, but, hopefully, serum drug concentrations
will be high enough so that the patient will experience
the pharmacological effect of the drug.

62
1. Plot log(C) vs. time
2. Plot the best-fit line
3. Extrapolate to the Y-axis intercept (to estimate
initial concentration, C0)
4. Estimate Vd:
!
Vd =
"
7
Log Co

6.8

6.6

6.4

6.2

6
Log Co
5.8
0 1 2 3 4 5 6

Time 63
 The half-life describes how quickly drug serum
concentrations decrease in a patient after a medication
is administered
 dimension of half-life is time (hour, minute, day, etc.).
 With first-order elimination, the rate of elimination is
directly proportional to the serum drug concentration.
There is a linear relationship between rate of
elimination and serum drug concentration.
 The elimination rate constant (K) represents the
fraction of drug eliminated per unit of time.

64
In first-order elimination, the rate of elimination is directly proportional
to the serum drug concentration.
The elimination rate constant (K) represents the fraction of drug
eliminated per unit of time.
For first-order kinetics:
dC/dt = - K C
By integration:
C = C o – e –Kt
ln C = ln Co - K t
N.B.: 2.303 log N = ln N
log C = log Co – Kt/2.303

65
Slope =

t1/2 = ln 2/K t1/2 = 0.693 / K

.

66
 * The half-life and elimination rate constant are
known as dependent parameters because their values
depend on the clearance (TBC) and volume of
distribution (Vd) of the agent:
t1/2 = (0.693 ⋅ Vd)/Cl as K = TBC/Vd.

* Because the values for clearance and volume of

distribution depend solely on physiological parameters
and can vary independently of each other, they are
known as independent parameters.

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Clearance is the volume of serum or blood
completely cleared of the drug per unit time.
TBC = K . Vd
$%& ' ( /*+&
MD = Css ⋅ TBC
Clearance (TBC) is the most important
pharmacokinetic parameter because it determines
the maintenance dose (MD) that is required to obtain
a given steady-state serum concentration (Css)
This range of steady-state concentrations is known
as the therapeutic range for the drug.
68
 an initial guideline for drug concentrations in a
specific patient
For example, the therapeutic range for theophylline
is generally accepted as 10–20 μg/mL for the treatment
of asthma. If it were known that the theophylline
clearance for a patient equaled 3 L/h and the desired
steady-state theophylline serum concentration was 10
μg/mL, the theophylline maintenance dose to achieve
this concentration would be 30 mg/h.
69
Fraction of dose remaining is given by the following
equation (F = X(t)/X0), where X(t): the amount at
any time & X0: the amount at zero time.
One half life later, 1/2 of the dose will remain. After
additional half life (1/4 of the dose will remain)… and
so on. A simple equation that relates the fraction
remaining of intravenous bolus dose (Q) which is left

after half-lives have elapsed is: Q = (1/2) n

Where n is the number of half-lives.

70
1. Predicting Plasma Concentrations

Example 1: A 20-mg dose of a drug was administered

as an intravenous bolus injection. The drug has the
following pharmacokinetic parameters: k = 0.1 h−1 and
Vd = 20 L

1. Calculate the initial concentration (C0 )

71
◦ Calculate the plasma concentration at 3 h

1. Calculate the plasma concentration at 3 h

C  C 0  e  Kt  1  e -(0.1)(3)  0.74 mg/L

2. Duration of Action
Example 2: Continuing with the drug used in
Example 1, if the therapeutic range is between 5 and
0.3 mg/L, how long are the plasma concentrations in
the therapeutic range?

72
 As indicated in the diagram C0 =1 mg/L. Thus, at
time zero the plasma concentration is in the therapeutic
range. The plasma concentration will remain
therapeutic until it falls to the MEC (0.3 mg/L). At
what time does this occur?

3. Value of a Dose to Give a Desired Initial Plasma

Concentration
 Example 3: Continuing with the drug used in Examples 1 and 2, If the initial Cp of 1
mg/L is unsatisfactory, Calculate a dose to provide an initial plasma concentration of 5
mg/L.
dose dose  C 0  Vd
C0 
Vd
mg
dose  5  20 L  100 mg
L
73
74
 Example 4:
 10 mg metoclopramide was administered
intravenously to a 72 kg patient. The minimum plasma
concentration required to cause significant
enhancement of gastric emptying is 50 ng/mL. The
following plasma concentrations were observed after
analysis of the specimen.
Time (hr) Conc. (ng/ml)

1 90.0
2 68.0
4 40.0
6 21.5
8 12.0
10 7.0

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Calculate the biological half-life of the drug
elimination (t½), the overall elimination rate constant
(K), the volume (Vd), the coefficient of distribution and
the duration of action (td)

The elimination rate constant can be obtained from

the slope:

76
 K  Slope  2.303
1
 (0.13481)  (2.303)  0.286 hr
 the biological half-life of the drug elimination (t½):

 The volume of distribution (Vd):

77
 the coefficient of distribution = Vd/wt =83 L/ 72
kg= 1.15 L/kg
 The duration of action (td). td is the time needed for
the concentration to get to 50 ng/ml :

78
 Example 5:
 An adult male patient was given the first dose of an antibiotic at
6:00 AM. At 12:00 noon the plasma level of the drug was measured
and reported as 5 µg/ml. The drug is known to follow the one
compartment model with a half-life of 6 hours. The recommended
dosage regimen of this drug is 250 mg q.i.d. the minimum inhibitory
concentration is 3 µg/ml. Calculate the following:
• Apparent volume of distribution
• Duration of action of the first dose
• Total body clearance
• Fraction of the dose in the body 5 hours after the injection
• Total amount in the body 5 hours after the injection
• Cumulative amount eliminated 5 hours after the injection
• Total amount in the body immediately after injection of a second
dose at 12:00 noon
• Duration of action of first dose only if dose administered at 6:00
AM was 500 mg.

79
  Elimination rate constant:

 Initial concentration:
• The conc. at 12:00 noon (6 hrs after the first dose)
is 5 µg/ml:

80
  Apparent volume of distribution: C(t=6hrs)= 5 ug/ml. Since
the half-life is 6 hrs, C0 = 10 ug/ml.

Duration of action of the first dose

 Duration of action of the first dose Total body clearance

C   10
ln 0  ln 
t   C *  3  10.42 hr
K 0.1155
Fraction of the dose in the body 5 hours after the
injection

81
 Fraction of the dose in the body 5 hours after the
injection

 Total amount in the body 5 hours after the injection

= (0.56)(250 mg) = 140 mg
 Cumulative amount eliminated 5 hours after the
injection = dose – amount in the body = 250 – 140 =
110 mg
 Total amount in the body immediately after
injection of a second dose at 12:00 noon

82
The main advantage for giving a drug by IV infusion
is that
(1) IV infusion allows precise control of plasma drug
concentrations to fit the individual needs of the patient.

(2) For drugs with a narrow therapeutic window (eg,

heparin), IV infusion maintains an effective constant
plasma drug concentration by eliminating wide
fluctuations between the peak (maximum) and trough
(minimum) plasma drug concentration.

83
 (3) The IV infusion of drugs, such as antibiotics, may
be given with IV fluids that include electrolytes and
nutrients.

(4) The duration of drug therapy may be maintained or

terminated as needed using IV infusion.

*If the drug is infused slowly through a vein into the

plasma, it follow a constant or zero-order rate.*

84
 At steady state, the rate of drug leaving the body is equal
to the rate of drug (infusion rate) entering the body.
at steady state, the rate of change in the plasma drug
concentration, dA/dt = 0, The steady state principle is also
known the plateau principle.
Rate of in = rate of out
Infusion rate = elimination rate
R Or K0 = K Ass = K.Vd Css = TBC. Css
This relationship shows that the plasma concentration at
steady state is proportional to the rate of infusion (i.e. the
higher the rate of infusion, the higher the SS plasma conc.)
and inversely proportional to drug clearance (i.e. the higher
the drug clearance, the lower the SS plasma conc.).

85
During infusion (Before steady state)

During infusion (At steady state)

Or Cp= K0/TBC

where K0 is the infusion rate, K is the elimination rate

constant, and Vd is the volume of distribution.
87
At steady state the input rate (infusion
rate) is equal to the elimination rate.
The elimination rate must be first order
kinetic. This characteristic of steady state
is valid for all drugs regardless to the
pharmacokinetic behavior or the route of
administration.

88
89
Fraction achieved of steady state concentration (Fss)
t
 1  t 0. 5 Fss 1e
Kt
OR Fss  1   
2
Time needed to achieve steady state: time needed to get to a certain fraction of
steady state depends on the half-life of the drug (not the infusion rate)

t   1 .44   t 0 .5  ln(1  FSS )

90
• Example: What is the minimum number of half-lives
needed to achieve at least 95% of steady state?

• At least 5 half-lives are needed to get to 95%

of steady state
• • Mathematically, the time to reach true steady-state drug
concentration, C SS, would take an infinite time. The time
required to reach the steady-state drug concentration in the
plasma is dependent on the elimination rate constant
of the drug for a constant volume of
distribution.
91
• Thus, the time for a drug whose t 1/2 is 6 hours to
reach at least 95% of the steady-state plasma drug
concentration will be 5t 1/2, or 5 x 6 hours = 30 hours.

• *A generally accepted rule is that about 5 half-

lives of continuous drug administration at a
constant rate are required before plasma
concentration reaches its steady state value.*

*Because steady state value is the therapeutic value

so we need a loading dose to accelerate the reaching
to the steady state value at zero time.*

92
when immediate drug effect is required and immediate
achievement of therapeutic drug concentrations is necessary
such as in emergency situations
In this ease, administration of a loading dose will be necessary.
93
To achieve a target steady state conc (Css) the following
equations can be used:
– For the infusion rate:

– For the loading dose:

– The loading dose, LD, or initial bolus dose of a drug, is
used to obtain desired concentrations (steady state) as
rapidly as possible.

The concentration resulting from both the bolus and the

infusion can be described as:
94
The concentration resulting from
both the bolus and the infusion can
be described as:

Ctotal =Cinfusion + Cbolus

95
The rate of infusion of a drug is sometimes changed
during therapy because of excessive toxicity or an
inadequate therapeutic response. If the object of the
change is to produce a new plateau, then the time to go
from one plateau to another whether higher or lower
depends solely on the half-life of the drug.

96
 K can be estimated using post infusion data by:
– Plotting log(Conc) vs. time
– From the slope estimate K:

Volume of distribution calculation using post

infusion data:

If you reached steady state conc (C* = CSS):

97
If you did not reached steady state (C* = CSS(1-e-kT)):

98
Example:
Following a two-hour infusion of 100 mg/hr plasma
was collected and analysed for drug concentration.
Calculate k and V.

Time relative to infusion

1 3 7 10 16 22
cessation (hr)
Cp (mg/L) 12 9 8 5 3.9 1.7

99
 Post infusion data

1.2

1
y = -0.0378x + 1.1144
R2 = 0.9664
Log(Conc) mg/L

0.8

0.6

0.4

0.2

0
0 5 10 15 20 25
Time (hr)

10
0
• From the slope, K is estimated to be:

From the intercept, C* is estimated to be:

Since we did not get to steady state:

10
1
 CONTENTS
• Dosage regimen
 • Objectives of dose regimen
 • Therapeutic drug monitoring
 • Multiple dosage regimen
 • Multiple dosing with respect to I.V.
 • Multiple dosing with respect to Oral route.
 • Concept of loading dose, maintenance dose.
 • Drug accumulation

102
 Dosage regimen
It is defined as the manner in which a drug is
taken.
For certain analgesics, hypnotics, anti-emetics etc. a
single dose may provide an effective treatment.
But the duration of most illness is longer than the
therapeutic effect produced by a single dose.

In such cases drugs are required to be taken on a

repetitive basis over a period of time.
10
3
 When the duration of treatment of disease is smaller
than the therapeutic activity of drug, single dose are
given e.g. Aspirin

10
4
 When the duration of treatment of disease is larger than
the therapeutic effect of drug, Multiple dosage regimen
are given e.g. antibiotics

10
5
 When an oral multiple dosing regimen is followed,
plasma conc. will increase, reach a maximum and
begin to decline. A 2nd dose will be administered
before all of the absorbed drug from 1st dose is
eliminated.
 Consequently plasma conc. resulting from 2nd dose
will be higher than from 1st dose. This increase in conc.
with dose will continue to occur until a steady state is
reach at which rate of drug entry into the body = rate
of exit
10
6
10
7
Multiple dosing with respect to I.V.
 On repeated drug administration, the plasma conc.
will be added upon for each dose interval giving a
plateau or steady state with the plasma conc.
fluctuating between a minimum and maximum

10
8
10
9
 when the drug dose is administered at the beginning
of the dosing interval and the drug concentration
increases from Cpmin ss to Cpmax ss, the drug
concentration has to return back to Cpmin at the end of
the dosing interval.

11
0
For a drug that is eliminated by first-
order process during multiple IV administration
of similar doses, D, administered every fixed dosing
interval, τ, the amount of drug in the body after
administration of the first dose is D. The amount of the
drug in the body before administration of the second
dose is De− kτ. If this continued, At steady state the
amount of the drug in the body after drug
administration, A∞ max = D (1+e− kτ+ De− 2kτ.+ De−
3kτ+De−4 kτ.

11
1
After single rapid IV injection,
DB = D0e-k t
If the τ is the dosing interval, then amount
of drug
remaining in the body after several hr,
DB= D0e-k τ
The fraction of the Dose remaining in the
body
f = DB/D0 = e -k τ 11
2
This is an infinite series that can be solved as
A∞ max 234
1

A∞ min A∞ max . 7 89

A∞ max A∞ min :;<7

where k is the first-order elimination rate constant.
Dividing these Equations by Vd, the equation
for the maximum plasma drug concentration
can be obtained:

11
3
 '
=>∞ ?@A EF
BCD
=>∞ ?GH =>∞ ?@A . E

' (
=>∞ IJ =>∞ ?GH
BC
similar group of expressions can be written to relate the
maximum and minimum plasma drug concentration at
steady state dur-ing multiple extravascular drug
administration when the drug absorption is rapid:
K'
=>∞ ?@A 2 EF
BCD
K' (
And & ∞ IJ & ∞ ILM
BC

11
4
 There are two main parameters that can be adjusted in
developing a dosage regimen:
(1) The size o f the drug dose

(2) The frequency of drug administration (ie, the time

interval between doses).

If the drug is administered at a fixed dose and a fixed dosage

interval, as is the case with multiple-dose regimens, the amount of
drug in the body will increase and then elimination occur. When
the second dose is given after a time interval shorter than the time
required to "completely" eliminate the previous dose, drug
accumulation will occur in the body.

115
 Drug Accumulation –

When the drug is administered at a fixed dose and a

fixed dosing interval, “accumulation occur because
drug from previous dose has not been remove.”
Accumulation of drug depend upon the dosing
interval and elimination half life and is independent
of the dose size.
Accumulation index = 1
1 – e- KE τ
τ= Dosing interval
KE = Elimination rate constant

11
6
•The degree of fluctuation depends on the dosage size,
the dosing interval, the absorption rate if given IM, or
oral, and the disposition rate of the drug.

1. The time required to reach steady state is dependent

on the half-life of the drug.

2. Generally, it takes five to six times the elimination

half-life of the drug to reach steady state.

11
7
3. the drug has to be repeatedly admin-istered for a
period equal to five to six half-lives to achieve steady
state. The longer the drug half-life the longer it takes to
reach steady state.

11
8
The loading dose is a dose larger than the
maintenance dose administered at the initiation of
therapy to achieve faster approach to steady state

11
9
 The loading dose is calculated from the desired plasma
drug concentration and the Vd of the drug. The
desired drug concentration is usually a drug concentration
within the therapeutic range:
Loading dose = Cp desired × Vd
Oral Loading Dose
Loading dose=(Cp desired ×Vd)/F
The average steady-state plasma drug
concentration is dependent on the dosing rate
(FD/τ) and the total body clearance of the drug.
Again, the loading dose does not affect the
steady-state concentration. 12
0
 Is the difference between the MEC and the MTC is
large or small (therapeutic index)? (if small
therapeutic index exists, frequent administration of
small doses will be necessary to avoid large
fluctuation in plasma concentration)
Is there a compliance problem with the drug? So,
reducing frequency may be recommended
 Is there a delayed response or tolerance to the action
of the drug as therapy progress? This will require
periodic evaluation of the pharmacological
response.
12
1
 Is the drug used in situations that require an
immediate effect? This will require the
administration of loading dose.
 Does the drug have a long or short half-life? This
will determine the frequency of administration
(dosing interval Ʈ)
Is the elimination of the drug affected by age or by
disease state? this will determine the dose according
to the patient condition.

12
2
this equation represents the relationship between
the rate of dosing (FD/τ) and the Average
concentration in the body during dosing interval at
steady state:

123
Average concentration at steady state:

After single dose AUC=FD/KVd

Therefore,

It depend on bioavailability , dose &

clearance. It is not the mean value of Cpss
max & Cpss min.

12
4
- The time required to reach to a certain fraction of the
steady-state level is given by:

Time required to achieve steady-state depends on the half-

life and is independent of the rate of dosing and the
clearance
To get to 95% of the steady-state: 5 half-lives are needed
To get to 99% of the steady-state: 7 half-lives are needed
Different doses regimen have the same average steady state
conc: The same dosing rate (Dose/ Ʈ).

12
5
Drug kinetic following
single oral dose
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Outlines
 Calculate plasma drug concentration at any given time after
the administration of an extravascular dose of drug.
 Employ residual method & extrapolation techniques to
characterize the absorption phase

 Calculate peak plasma drug concentration, cp/max, and the

time, tmax, at which this occurs
 Lag time in a drug’s absorption, Onset of action & Duration
of response
 Normal kinetics & Flip-flop kinetics
Oral absorption
 Absorption phase:
absorption rate more
than elimination rate
 Plateau (elimination rate
equal absorption rate)
 Postabsorption phase:
elimination rate more
than absorption rate
 Elimination phase: no
significant absorption
occur (only elimination
process)
Oral absorption
 The tmax is independent of dose and
is dependent on the rate constants
for absorption (ka) and elimination (k)
(rate of absorption)
 At Cmax, sometimes called peak
concentration, the rate of drug
absorbed is equal to the rate of drug
eliminated. Therefore, the net rate of
concentration change is equal to
zero. (Intensity of absorption)

 AUC is a measure of the body’s

exposure to a drug
One-compartment pharmacokinetic model for
first-order drug absorption and first-order
drug elimination

Absorption Elimination
Drug in the body
process (Ka) (X) process (K)

dX
 KaXa  KX
dt
X: drug amount in the body, Xa: drug amount in
the GI available for absorption, K: elimination
rate constant, and Ka: absorption rate constant
Mathematical model
 Assuming first-order absorption and first-order
elimination, the amount of drug (Ao or Xo or D)
in the body is described by:

KaFA
Cp 
Vd ( Ka  K )
e 
 Kt
e  Kat

F (Bioavailability): Fraction of the dose that
reach systemic circulation
At time zero, no drug in blood (Cpo= zero)
Determination of the Model
Parameters
 K
 Elimination half life
 Ka
 Absorption half life
 tmax and Cmax
 Clearance
 Volume of distribution
 AUC
Oral absorption
KaFXo
Cp 
Vd ( Ka  K )
e  Kt
e  Kat

This portion measure This portion measure
the elimination process the absorption process
Terminal phase (elimination)
 Because in the
Elimination phase no
significant absorption
occur (only elimination
process), the plasma
concentration
equation can be
simplified into:
KaFXo
Cp 
Vd ( Ka  K )
 
e  Kt
Method of residuals
 The method of residuals is a graphical method used
to determine the drug absorption rate constant and
has the following assumptions:
 The absorption rate constant is larger than the elimination rate
constant ,that is, Ka>K.
 Both drug absorption and elimination follow first-order kinetics
 The drug pharmacokinetics follow one-compartment model
 The idea of the method of residuals is to characterize the
drug elimination rate from the terminal elimination phase
of the plasma drug concentration—time profile after a
single oral administration.
 Then the contribution of the drug absorption rate and the
drug elimination rate during the absorption phase can be
separated
Method of residuals
1. The plasma drug concentration is plotted against their
corresponding time values on the semi-log scale
2. The slope of the line that represents the elimination phase is
calculated. The slope of this line is equal to –k/2.303. The
terminal line is back extrapolated to the y-axis

3. At least three Points on the extrapolated line at three different

time values during the absorption Phase of the drug are taken.
Vertical lines from the points on the extrapolated line are dropped
to determine the corresponding points (at the same time values)
on the plasma drug concentration-time curve

4. The differences between the y-coordinate values of the points on

the extrapolated line and corresponding y-coordinate values on
the plasma drug concentration-time curve are calculated. The
values of these differences are the residuals
Method of residuals
 The values of the residuals are plotted versus their
corresponding time values for each residual on the same
graph. A straight line should be obtained with a slope of
-ka/2.303.

 The extrapolated line representing the elimination phase

and the residuals versus time line should have the same
y-intercept. This is because the equations that describe
the two lines have the same coefficient, so substituting
time by zero in the two equations should give the same
term.
Method of residuals
1- From the terminal phase determine the
elimination rate constant

Terminal line
Method of residuals
2- Construct the residual line by taking the difference
between the terminal line and the observed conc.

Residual line
Method of residuals
3- Estimate the absorption rate constant from the slope of
the residual line

Residual line
Example
 After oral administration of a single dose of an
antibiotic, the following concentrations were
measured: Time (h)
Drug Concentration
(mg/L)
0 0
0.2 88
0.5 185
1.0 277
2.0 321
2.5 311
4.0 246
6.0 161
8.0 102

Calculate the first-order absorption rate constant.

Answer
 Plot the plasma concentration–time profile
and follow the procedures for the method
of residuals as in following Figure.
Calculate the residuals.
Line of Residuals
Time (h) Curve
Elimination (mg/L)
0.2 660 88 660− 88 = 572
0.5 590 185 590− 185 = 405
1.0 510 277 510− 277 = 233
The line resulting from plotting the residuals - 0.367 h-1 = Ka/2.303
Ka = 0.846 h-1
Determination of the Model
Parameters
 Elimination half life = 0.693/K
 Absorption half life = 0.693/Ka
 tmax (or tp): 2 .303 Ka
t  log
max (Ka  K) K

 tmax = Ln Ka – LnK / Ka – K = Ln (ka/k)/(Ka-k)

 The tmax is independent of dose and is
dependent on the rate constants for absorption
(ka) and elimination (k) (rate of absorption)

21
Determination of the Model
Parameters
 Cmax (Conc at t = tmax)

KaFD
C max 
Vd(Ka  K )

e Kt max  e Kat max 
 At Cmax, sometimes called peak concentration, the
rate of drug absorbed is equal to the rate of drug
eliminated. Therefore, the net rate of concentration
change is equal to zero
Determination of the Model Parameters

 AUC FD
AUC 
KVd

 Volume of Distribution
FD
Vd 
K . AUC
 Clearance FD
Cl 
AUC
Example 2
 The presented table gives the Time Conc
plasma drug concentrations that (hr) (mg/L)
were obtained following the oral 0.25 3.77
administration of 500 mg dose of 0.5 6.53
drug X. Assuming that drug X 0.75 8.49
follows normal pharmacokinetics, 1.5 11.32
determine the following: 2 11.7
 Elimination rate constant 3 10.92
 Absorption rate constant 10 2.96
 Volume of distribution (normalized for 24 0.18
bioavailability)
30 0.05
Example 2
Determine elimination phase
1.5

1
Elimination phase
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
Example 2:
Determine K
1.5
Terminal line equation:
y = -0.0883x + 1.359
1 2
R = 0.9998

K =-slope*2.303 =0.0883*2.303
log (Conc) mg/L

0.5
K= 0.2 hr-1

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
Example 2:
Extrapolate the terminal line to cross the y-axis
1.5

y = -0.0883x + 1.359
1 2
R = 0.9998
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
Example 2:
Draw the residual line
1.5

1
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5

-1

-1.5
time (hr)
Example 2:
Determine Ka
1.5

1
log (Conc) mg/L

0.5

0
0 5 10 15 20 25 30 35

-0.5
Residual line equation:
y = -0.3814x + 1.3372
-1 2
R = 0.9988

Ka =-slope*2.303 =0.03814*2.303
-1.5
Ka= 0.878 hr-1
time (hr)
Example 2
 Volume of distribution (normalized for
bioavailability):
 From the terminal line best fit line,
intercept = 1.359.
Ka  F  D
Intercept
10 
Vd ( Ka  K )
Vd Ka  D 0.878 * 500
  Intercept  1.359  28.3 L
F 10 ( Ka  K ) 10 (0.878  0.2)
Effect of Ka on tmax, Cmax, and
AUC
Changing Ka ( K unchanged)
 Increasing the
absorption rate
constant (Ka) results
in:
 Shorter tmax
 Higher Cmax
 Unchanged AUC
Effect of K on tmax, Cmax, and
AUC
Changing K ( Ka unchanged)
 Increasing the
elimination rate
constant (K) results
in:
 Shorter tmax
 Lower Cmax
 Lower AUC

32
 Effect F on tmax, Cmax, and AUC
300
F=1
 Increasing the bioavailability
250 results in:
 Unchanged tmax
Concentration

200
 Higher Cmax
150
F = 0.5  Higher AUC

100

50 F = 0.25

0
0 20 40 60 80 100
time
Example
 A 500-mg dose of the sulfonamide sulfamethoxazole
is administered as an oral tablet to a human subject.
Eighty percent of the drug is absorbed, and the
balance is excreted unchanged in feces. The drug
distributes into an apparently homogeneous body
volume of 12 L, and has an absorption half-life of 15
hr and overall elimination half-life of 12 h.
1) Calculate the following:
(i) AUC0→∞,(ii) tmax and (iii) C max.
2) Recalculate the values in Problem 1 if all parameter
values remained unchanged, but the elimination half-
life was increased to 18 h.
Example
 Estimate k and ka:
e lim in 1
k  0.693 t 1/ 2  0.693 12  0.058 hr

k a  0.693 t1abs
/2  0 .693 15  0.046 hr 1

 Estimate AUC:
FD 0.8  500
AUC    575 mg  hr/L
KVd 0.058*12
Example
 Estimate tmax:
tmax = Ln Ka – LnK / Ka – K
= ((-3.07911- (-2.84731))/ (0.046-0.058)=19.32 hr

2 . 303 Ka
t max  log
(Ka  K) K
2 . 303 0 . 046
 log  19 . 32 hr
( 0 . 046  0 . 058 ) 0 . 058
Example
 Estimate Cmax:
KaFXo
C max 
Vd ( Ka  K )

e  Kt max  e  Kat max 
C max 
12(0.046  0.058)
e
0.046  0.8 * 500 0.058*19.32 0.046*19.32
e 
C max  10.9 mg/L
Example
Recalculate the values in Problem 1 if all parameter values remained
unchanged, but the elimination half-life was increased to 18 h

k  0.039 hr 1
t max  23 . 5 hr

AUC  855 mg  hr/L

C max  13.3 mg/L
Example
 A single oral dose (100 mg) of an antibiotic was
given to an adult male patient (43 years, 72 kg). From
the literature, the pharmacokinetics of this drug fit a
one-compartment open model. The equation that best
fits the pharmacokinetics of the drug is
Cp = 45 (e-0.17t-e-1.5t)
 From the equation above, calculate (a)t max, (b)C max,
and (c)t 1/2 for the drug in this patient. Assume C p is
in µg/mL and the first-order rate constants are in
hours– 1.
Lag Time:
 This delay time before starting drug
absorption is known as the lag time.
 can be short and does not significantly affect the
plasma drug concentration–time profile.
 However, the lag time can be long such as after
administration of enteric coated formulations
(formulation factors)
 Physiological factors : Gastric emptying rate
& intestinal motility
 In this case, the dosage form disintegration, drug
dissolution, and drug absorption start after the
dosage form reaches the small intestine, which
can take hours, especially if the drug is
administered with food.
 Onset of effect: Time required to reach MEC.
 Duration of Response: The period of time in
which plasma conc. is higher than MEC.
Normal kinetics vs. Flip-flop kinetics
 In a series of two consecutive, irreversible first-order rate
processes such as absorption of a drug from the
intestine and its subsequent systemic elimination, either
step can be rate-limiting in the overall elimination
process
 In general, ka of a drug after oral administration is
greater than k so that elimination of the drug from the
body after oral administration is governed primarily by
how fast it can be removed once it enters the systemic
circulation
 In this case (e.g., ka > k), a plasma concentration-time
profile after oral dosing exhibits a terminal half-life similar
to that after intravenous injection
Normal kinetics vs. Flip-flop kinetics
 When ka is much smaller than k (e.g., k > ka ) , drug
disappearance from the body becomes governed by the
rate of absorption rather than by the rate of elimination,
and absorption t1/2 becomes longer than elimination t1/2.
This phenomenon is called “flip-flop kinetics”
 When a drug is released at a sustained rate instead
of immediate release

Summary
Ka > K: Normal Kinetics (the slope
of the terminal phase represent K)
K > Ka: Flip-Flop Kinetics (the slope
of the terminal phase represent Ka)
Distinguishing between Normal and
Flip-Flop kinetics

IV bolus data is needed to differentiate between

Normal and Flip-Flop kinetics
 Normal Kinetics example
Difference observed in the
absorption phase Normal kinetics

Theophylline conc-time profile

resulting from the administration
of two 130 mg tablets:
Dissolved in 500 mL water and taken
on an empty stomach

Taken on an empty stomach

Taken after meal

 Flip-Flop kinetics example
Difference observed in the terminal
phase Flip-flop kinetics Penicillin G was
administered IM as an:
Aqueous solution (I.M)

Procaine penicillin in oil (P-I.M)

Procaine penicillin in oil with
aluminum monostearate (AP-
I.M)
Wagner–Nelson Method
 The Wagner–Nelson method is a method that
can be used to determine the absorption rate
constant for drugs when their absorption follows
zero-order kinetics or first-order kinetics.

 The Wagner–Nelson method uses the

relationship between the fractions of the
administered dose remaining to be absorbed at
different time points to determine the absorption
rate constant.
Bioavailability
&
Bioequivalence
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Outlines
 Bioavailability
 Absolute Bioavailability
 Relative Bioavailability
 AUC calculation using Trapezoidal
rule
 Bioequivalence
Introduction
 The most important property of any non-intravenous
dosage form, intended to treat a systemic condition, is
the ability to deliver the active ingredient to the
bloodstream in an amount sufficient to cause the desired
response
 This property of a dosage form has historically been
identified as physiologic availability, biologic availability
or bioavailability
 Bioavailability captures two essential features, namely
how fast the drug enters the systemic circulation (rate of
absorption) and how much of the nominal strength
enters the body (extent of absorption)

3
Introduction
 Given that the therapeutic effect is a function
of the drug concentration in a patient's blood,
these two properties of non-intravenous
dosage forms are, in principle, important in
identifying the response to a drug dose:
1. Onset of response is linked to the rate of drug
absorption whereas the time-dependent
2. Extent of response is linked to the extent of
drug absorption & elimination.

4
Bioavailability
 ‘‘The relative amount (the extent) of an
administered dose that reaches the
general circulation and the rate at which
this occurs’’ (American Pharmaceutical
Association, 1972)
 The rate and the extent of drug that
reach systemic circulation

5
Bioavailability studies importance:
 Bioavailability studies provide an estimate of the fraction
of the orally administered dose that is absorbed into the
systemic circulation when compared to the bioavailability
for an intravenous dosage form that is completely
available

 Bioavailability studies provide other useful information

that is important to establish dosage regimens.

 Bioavailability studies provide indirect information

regarding the presystemic and systemic metabolism of
the drug and the role of transporters such as p-
glycoproteins

6
Bioavailability studies importance:
 Bioavailability studies designed to study the food
effect on drug absorption

 Such studies when designed appropriately provide

information on the linearity or nonlinearity in the
pharmacokinetics of the drug and the dose
proportionality

 Bioavailability studies provide information regarding

the performance of the formulation and
subsequently are a means to document product
quality

7
Factors affecting the bioavailability
 Bioavailability following oral doses may vary
because of either patient-related or drug &
dosage-form-related factors
 Patient factors can include age, disease, genetic,
the nature and timing of meals, and
gastrointestinal physiology
 The drug & dosage form factors include 1) the
chemical form of the drug (e.g. salt vs. acid), 2) its
physical properties (e.g. crystal structure, particle
size), and 3) an array of formulation (e.g. non-
active ingredients) and manufacturing (e.g. tablet
hardness) variables

8
Factors affecting bioavailability
1. Gastric emptying: Although not true in all cases,
increased gastric emptying generally enhances
bioavailability of orally administered drugs.
Gastric emptying depends on the following
factors:
 Volume of liquid & food intake
 pH of the stomach
 Intake of other drugs
 Age and weight of the patients
 Physical activity of the patients taking drug
 Various disease states

9
Factors affecting bioavailability
2. Presystemic and systemic metabolism —
Presystemic metabolism, which occurs during
first-pass metabolism, can decrease the
bioavailability of a drug. The following types of
metabolism are commonly seen:
 First-pass metabolism: First-pass metabolism occurs when an
absorbed drug passes directly through the liver before reaching
systemic circulation after oral administration.
 Intestinal metabolism: Drug metabolizes in the intestine itself or
during the passage through the intestinal wall.
 Hydrolysis of the drug in the stomach fluids.
 Transporters such as p-glycoprotein may influence the
bioavailability of a drug.

10
Factors affecting bioavailability
3. Complexation with other agents in the
gastrointestinal tract
4. Formulation factors, such as inert ingredients, the
manufacturing process and/or use of surfactants,
& dosage form (the bioavailability of the IV >IM >
S.C and in case of oral dosage form the
bioavailability of the solution > suspension >soft
capsule > hard capsule > tablet).
5. Drug related factors: Chemical and physical
properties; Lipophilicity & hydrophilicity.

11
 Bioavailability assessment methods
1. Direct measure of bioavailability:
 Based on Plasma Drug Concentrations

2. Indirect measure of bioavailability:

 Based on Urinary Excretion Data: This method can be used
only if urinary excretion of unchanged drug is the main
mechanism of elimination of the drug.

 Based on Acute Pharmacodynamic Effect:

This approach may be applicable when the drug is not intended to
be delivered into the bloodstream for systemic availability. It is an
indirect measure of bioavailability in cases where the analytical
method for assessing drug concentrations in the plasma or other
biological fluids cannot be developed.

12
To assess the bioavailability

 The tmax (rate of absorption)

 At Cmax, (Intensity of absorption)

 AUC is a measure of the body’s

exposure to a drug (The extent of
drug absorption and clearance)
Which formulation has higher
bioavailability?

14
Absolute bioavailability
 The systemic availability of the drug after
extravascular administration of the drug and is
measured by comparing the area under the drug
concentration–time curve after extravascular
administration to that after IV administration.

 Extravascular administration of the drug comprises

routes such as oral, rectal, subcutaneous, transdermal,
nasal, etc.

15
IV bolus
100

80
Concentration

Area under concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 16
Oral dosage form (product A)
100

80
Area under concentration
Concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 17
Absolute bioavailability
For the same dose
100 (IV vs. Oral), the
bioavailability is given
80
by: AUC oral
F
Concentration

60 AUC IV
AUCoral DoseIV
40 F  
AUC IV Doseoral
20
zero to 1
0
0 5 10 15 20 25 30
Time 18
Example
 If the AUC for an oral dose of a drug
administered by tablet is 4.5 mg/ml/hr, and
the intravenous dose is 11.2 mg/ml/hr,
calculate the bioavailability of the oral
dose of the drug?
F = 4.5 / 11.2 = 0.4 or 40%

19
Relative bioavailability
 The systemic availability of a drug from
one drug product (A) compared to another
drug product (B).
 It can be more or less than 1.

20
Oral dosage form (product A)
100

80
Area under concentration
Concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 21
Oral dosage form (product B)
100

80
Concentration

60 Area under concentration

curve (AUC)

40

20

0
0 5 10 15 20 25 30
Time 22
Relative bioavailability
100 For the same dose
(IV vs. Oral), the
80
bioavailability is given
Concentration

by:
60

AUCoral ( A)
40 F
AUCoral ( B )
20

0
0 5 10 15 20 25 30
Time 23
Practice Problem
 The bioavailability of a new investigational drug
was studied in 12 volunteers. Each volunteer
received either a single oral tablet containing
200 mg of the drug, 5 mL of a pure aqueous
solution containing 200 mg of the drug, or a
single IV bolus injection containing 200 mg of
the drug. The average AUC values are given in
the table below. From these data, calculate
 the relative bioavailability of the drug from the tablet
compared to the oral solution
 the absolute bioavailability of the drug from the tablet.

24
Practice Problem
Drug Product Dose (mg) AUC (ug. hr/mL)
Oral tablet 200 50
Oral solution 200 75
IV bolus injection 200 150

25
Area Under the Conc. Time Curve
(AUC) calculation
 Two methods:
 Model dependent: can be used only for one
compartment IV bolus
 Model independent: Can be used for any drug
with any route of administration

26
AUC calculation: Model dependent

 With one compartment model, first-order

elimination, and intravenous drug
administration, the AUC can be calculated
using:
Dose C0
AUC  
K Vd K

27
AUC calculation: Model
independent

28
‫)ﺷﺑﻪ ﺍﻟﻣﻧﺣﺭﻑ( ‪Trapezoidal rule‬‬
‫ﻣﺳﺎﺣﺔ ﺷﺑﻪ ﺍﻟﻣﻧﺣﺭﻑ=)ﻣﺟﻣﻭﻉ ﺍﻟﻘﺎﻋﺩﺗﻳﻥ‪×(2/‬ﺍﻻﺭﺗﻔﺎﻉ‬

‫‪29‬‬
AUC calculation: Model
independent
Area under tail (area between the last
observed concentration and infinity)
use the following equation:

C* C*
area 
K

30
Trapezoidal rule
 AUC = Sum of all trapezoids + area
under tail

 AUC = 1/2 (C0+C1) (t1-t0) + 1/2 (C1+C2)

(t2-t1) + 1/2 (C2+C3) (t3-t2) +1/2 (C3+C4) (t4-
t3) + C 4 (last)/k

31
Trapezoidal method

32
 Example
IV Bolus (250 mg) Oral Suspension Oral Capsule
Time (500 mg) (500 mg)
Conc. (mg/ml) Conc. (mg/ml) Conc. (mg/ml)
1 6.3 5.0 3.1
2 5.0 7.0 4.7
3 4.0 7.4 5.2
4 3.2 7.0 5.3
6 2.0 5.4 4.5
8 1.3 3.7 3.4
12 0.5 1.6 1.7

The half-life of this antibiotic is 3 h and the absorption process

is complete after 12 h of oral administration.
a. Calculate the absolute BA of the oral suspension and the oral capsule of
this antibiotic.
b. Calculate the BA of the oral capsule relative to the oral suspension of this
antibiotic.
33
Answer
 Calculation of the AUC after administration of 250 mg IV: Plot
the plasma concentration–time profile after IV administration on the
semilog scale and back extrapolate the resulting line to calculate the
initial plasma concentration Cpo. The Cpo is 8 mg/L and the first-
order elimination rate constant (k) is 0.693/3 h = 0.231 h−1.
 AUC IV= Cp0 / k= 8 /0.231 = 34.63 mg.h/L
 Calculation of the AUC after administration of 500 mg oral
suspension by the trapezoidal rule:

 AUC = 1/2 (C1t1) + 1/2(C1+C2) (t2-t1) + 1/2(C2+C3) (t3-t2) +

1/2(C3+C4) (t4-t3) + 1/2(C4+C5) (t5-t4) +1/2(C5+C6) (t6-t5) +
1/2(C6+C7) (t7-t6) + C Last/k

34
Calculation of the AUC after administration of 500
mg oral suspension by the trapezoidal rule:
 Area of trapezoid 1= ½*(0+5) (1-0)=2.5 mg.h/L
 Area of trapezoid 2= ½*(5+7) (2-1)=6 mg.h/L
 Area of trapezoid 3= ½*(7+7.4) (3-2)= 7.2 mg.h/L
 Area of trapezoid 4= ½*(7.4+7) (4-3)= 7.2mg.h/L
 Area of trapezoid 5= ½*(7+5.4) (6-4)= 12.4mg.h/L
 Area of trapezoid 6= ½*(5.4+3.7) (8-6)= 9.1 mg.h/L
 Area of trapezoid 7= ½*(3.7+1.6) (12-8)= 10.6 mg.h/L
 Area of tail= Clast/k = 1.6/0.231=6.93 mg.h/L
 Total AUC =2.5 + 6.0 + 7.2 + 7.2 + 12.4 + 9.1 + 10.6 +
6.93 = 61.93 mg. h/L

35
Calculation of the AUC after administration of 500
mg oral capsule by the trapezoidal rule:
 Area of trapezoid 1= ½*(0+3.1) (1-0)=1.55 mg.h/L
 Area of trapezoid 2= ½*(3.1+4.7) (2-1)=3.9 mg.h/L
 Area of trapezoid 3= ½*(4.7+5.2) (3-2)= 4.95 mg.h/L
 Area of trapezoid 4= ½*(5.2+5.3) (4-3)= 5.25 mg.h/L
 Area of trapezoid 5= ½*(5.3+4.5) (6-4)= 9.8 mg.h/L
 Area of trapezoid 6= ½*(4.5+3.4) (8-6)= 7.9 mg.h/L
 Area of trapezoid 7= ½*(3.4+1.7) (12-8)= 10.2 mg.h/L
 Area of tail= Clast/k = 1.7/0.231=7.36 mg.h/L
 Total AUC =1.55 + 3.9 + 4.95 + 5.25 + 9.8 + 7.9 + 10.2
+7.36 = 50.9 mg. h/L

36
Answer
 The absolute BA of the suspension (note that the doses
for the IV and the oral suspension are different):
61.93 250
F susp = × = .
34.63 500
 The absolute BA of the capsule (Note that the doses for
the IV and the oral capsule are different):
.
F cap = × = .
.
 b. The BA of the capsule relative to the suspension (the
dose is similar):
50.9 500
F relative = × = . %
61.93 500
&'() .,
 F relative = = = . %
&*+*) .-
37
Bioequivalence

38
Bioequivalence
 Pharmaceutical alternatives: Drug products that
contain the same therapeutic moiety but differ in dosage
form, strength, salt or ester of the active therapeutic
moiety.

 Pharmaceutical equivalents: Drug products that

contain the exact active ingredient (i.e., the same salt or
ester of the therapeutic moiety), identical strength, and
the same dosage form for the same route of
administration, but differ in shape, release mechanism,
labeling, scoring, and excipients including color, flavor,
and preservative.

39
 Bioequivalent products: Pharmaceutical equivalent
products with no significant difference in the rate and
extent to which the active ingredient becomes available at
the site of action when administered under similar
conditions in an appropriately designed study.
 Therapeutic equivalents: Drug products for the same
active ingredient that can be substituted with the full
expectation that the substituted product will produce the
same clinical effect and safety profile as the prescribed
product. Drug products are considered to be
therapeutically equivalent if they are pharmaceutical
equivalents and bioequivalents.
 Clinical Equivalence: The drug products provide identical
in vivo pharmacological response as measured by control
of the disease or symptoms.

40
 Criteria for waiver of the BA or BE

 Parenteral solutions intended solely for

administration by injection or ophthalmic or otic
solutions that contain the same active and
inactive ingredients in the same concentration
as an approved drug product.
 Products administered by inhalation as a gas, for
example, an inhalation anesthetic, that contain
the same active ingredient in the same dosage
form as an approved drug product.

41
 Criteria for waiver of the BA or BE

 Solutions for application to the skin (Topical

preparation), oral solutions, elixirs, syrups, tinctures,
solutions for aerosolization or nebulization, nasal
solutions, or similar other solubilized form that contain an
active drug ingredient in the same concentration and
dosage form as an approved drug product and contain
no inactive ingredient that can affect the in vivo BA of the
active ingredients.
 Drugs with local effect (Not absorbed from GIT)
(Antacids)

42
 Criteria for waiver of the BA or BE

 For example, immediate-release solid dosage forms of the

biopharmaceutics classification system (BCS) class I drugs
(highly soluble, highly permeable) have rapid and similar in
vitro dissolution characteristics.

 Rapid dissolution means at least 85% dissolution in 30 min in

900 mL at pHs 1.2, 4.5, and 6.8, while similar dissolution
profile can be evaluated by comparing the similarity factor (f2)
at the three pHs. Comparing the dissolution profile is not
necessary if the dissolution is 85% in less than 15 min.

43
 Pharmacokinetic approach to demonstrate
product bioequivalence:
 Study Design
 Repeated measures, cross-over and carry-over
designs:
 The administration of two or more treatments one after
the other in a specified or random order to the same
group of patients is called a crossover design or
change-over design
 Advantages
 They provide good precision for comparing treatments
because all sources of variability between subjects are
excluded from the experimental error. It is economic on
subjects. This is particularly important when only a few
subjects can be utilized for the experiments.
44
 Washout period
 The time interval between the 2 treatments is
called as WASHOUT PERIOD.

 It is required for the elimination of the

administered dose to avoid the carry over effect

 A washout period of 1 week was usually found

suitable in most cases (5 times half-life of the
used drug).

45
2. Subjects:
 Selection of subjects:
 Aim to minimize variability and permit detection of differences
between pharmaceutical products.
 The studies should normally be performed with healthy volunteers
24 volunteers (12 in each group).
 They should be screened for suitability by means of clinical
laboratory tests, review of medical history, and medical examination.
 Standardization of the study:
 Standardization of the diet, fluid intake and exercise is
recommended.
 The subjects should not take other medicines during a suitable
period before and during the study.
 Genetic pheno-typing:

46
 Characteristics to be investigated
 In most cases evaluation of bioavailability and
bioequivalence will be based upon the measured
concentrations of the parent compound.
 In some situations, measurements of an active or
inactive metabolite are carried out.
 The plasma concentration versus time curves is mostly
used to assess extent and rate of absorption.
 The use of urine excretion data may be advantageous in
determining the extent of drug input in case of products
predominately excreted renally.
 Specificity, accuracy and reproducibility of the methods
should be sufficient.
47
 Chemical analysis
 Reference and test product
 Data analysis
 Statistical analysis
 Acceptance range for pharmacokinetic parameters:
 1.AUC-ratio:
 It should lie within an acceptance interval of 0.80-1.25.
 2.Cmax-ratio:
 It should lie within an acceptance interval of 0.80-1.25.
 The wider interval must be 0.75-1.33.
 For tmax if there is a clinically relevant claim for rapid
release or action or signs related to adverse effects.

48
Two-compartment
Pharmacokinetic
Model
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Outlines
 Pharmacokinetic Model

 One Compartment Model

 Two Compartment Model

 Three Compartment Model

 Pharmacokinetic Models
 A model is a hypothesis enables using mathematical
terms to simulate the rate processes of drug absorption,
distribution, and elimination
 Compartment models are based on linear assumptions
using linear differential equations
 It enables Predict plasma, tissue, and urine drug levels
with any dosage regimen.
 The number of compartments in the model depends on
the rate of drug distribution to the different parts of
the body
Pharmacokinetic Models
one-compartment model
 If the drug in the systemic circulation is distributed
rapidly to all parts of the body, the body behaves as a
single compartment and the drug pharmacokinetic
behavior can be described by one-compartment.

 In this case the plasma and all perfused organs deal as

one unit (the central compartment)

 The drug is both added to and eliminated from a central

compartment.
One compartment open model
 The one-compartment open model offers the simplest
way to describe the process of drug distribution and
elimination in the body.

 This model assumes that the drug can enter or leave the
body (ie, the model is "open"), and the body acts like a
single, uniform compartment.

 The simplest route of drug administration from a

modeling perspective is a rapid intravenous injection (IV
bolus).

6
One compartment open model
 The simplest kinetic model that describes drug
disposition in the body is to consider that the
drug is injected all at once into a box, or
compartment, and that the drug distributes
instantaneously and homogenously throughout
the compartment.

 Drug elimination also occurs from the

compartment immediately after injection.

7
One compartment model

8
absorption Central elimination
compartment

Oral dose

elimination
Central
compartment

IV dose
One compartment:

10
One compartment:

IV bolus Elimination process

administration Drug amount in the
(dose = X0) Body (X) Elimination rate
constant (K)

Based on the assumption of first order elimination process

11
Two-compartment model
 While if the drug is distributed rapidly to some tissues
and organs and slowly to other tissues and organs, the
two-compartment pharmacokinetic model can be used to
describe the pharmacokinetic behavior of the drug in this
case.
 In a two-compartment model, drug can move between the
central ( plasma compartment and highly perfused organ)
to and from the tissue compartment (peripheral
compartment).
 In this model, in most cases, there is no elimination from
tissue compartment and the drug need to be transported
again to the plasma in order to be eliminated
 absorption
Peripheral
Central compartment
compartment
Oral dose

elimination

Central Peripheral
IV dose compartment compartment

elimination
Typical plasma concentration (Cp) versus time profiles for a
drug that obeys a two-compartment model following
intravenous bolus administration

y axis: normal scale y axis: logarithmic scale

A schematic representation of two-compartment models
consisting of a central and a peripheral compartment.
k12 is the first-order transfer rate constant from the central
compartment to the peripheral compartment and has units of time−1.
k21 is the first-order transfer rate constant from the peripheral
compartment to the central compartment and has units of time−1.
k10 is the first-order elimination rate constant from the central
compartment and has units of time−1.

k21
Central Peripheral
IV dose compartment compartment
(X1) (X2)
k12
k10

elimination
Assumptions of the model
 Upon drug absorption there is instantaneous
distribution of drug throughout the central
compartment (sampling compartment) having a
volume V1 (Vc)
 Transfer of drug from the central compartment to
the peripheral compartment is by a first-order
process
 Transfer of drug from of drug from the peripheral
compartment to the central compartment is by a
first-order process
Drug concentrations in the two compartments
following a single i.v. bolus injection
A. At zero time, there is no
drug in the peripheral
compartment
B. The amount of the drug in
the central compartment
decreases rapidly due to
drug distribution and
elimination
C. Some drug in peripheral
compartment come back to
the central compartment
but the net transfer from
central to the peripheral till
equilibrium (maximum
conc. In the peripheral
compartment)
Drug concentrations in the two compartments
following a single i.v. bolus injection
D. Elimination occur
from central
compartment, so
amount of drug in it
decrease slowly
leads to increase the
rate of transfer from
the peripheral to the
central compartment,
so the net drug
transfer from the
peripheral to the
central compartment.
Parameters of the two-compartment
pharmacokinetic model
 Vc is the volume of the central compartment and has units of volume.
This term relates the administered dose to the initial plasma drug
concentration (central compartment concentration) after administration of
a single IV dose: Cp0= Dose/Vc
 Vdss: is the volume of distribution of the drug at steady state and has
units of volume. This term relates the amount of the drug in the body and
the plasma drug concentration at steady state: Amount of the drug in the
body at steady state = Vdss Cpss
 Vdβ : is the volume of distribution during the elimination phase and has
units of volume. This term relates the amount of the drug in the body
and the plasma drug concentration during the elimination phase (β-
phase): Amount of the drug in the body during the elimination phase =
Vdβ Cpβ-phase.
 K12
X1 X2
Central K21 peripheral

K10

dX 1
 K 21 X 2  K12 X 1  K10 X 1
dt
dX 2
 K12 X 1  K 21 X 2
dt
Distribution rate from X1 to X2 = K12 X 1
Distribution rate from X2 to X1 = K 21 X 2
Elimination rate = K10 X 1
 X 0 (  K 21 ) t X 0 ( K 21   )  t Amount in the
X1  e  e central compartment
   
X 0 (  K 21 )  t X 0 ( K 21   )   t Conc in the central
C1  e  e compartment
VC (   ) VC (   )
VC is the volume of the central compartment

Cp = Ae−αt + Be−βt biexponential

Xo (  K 21) Xo ( K 21   )
A B
Vc (   ) Vc (   )

XoK 12  βt Amount in the

X2  (e  e αt ) peripheral compartment
(α  β)
 Parameters of the two-compartment
pharmacokinetic model
 A and B are the hybrid coefficients and have units of
concentrations.
 α is the hybrid first-order rate constant for the distribution
process and has units of time−1.
 β is the hybrid first-order rate constant for the elimination
process and has units of time−1.
 t1/2 α is the half-life for the distribution phase and has
units of time.
 t1/2 β is the half-life for the elimination phase and has
units of time.
 Determination of the postdistribution rate constant (β) and
the coefficient (B)

 Postdistribution
phase to
determine:
1. Determine β from
the graph by using
the slope
2. The y-axis
intercept of the
extrapolated line is
B
Determination of the distribution rate constant
(α) and the coefficient (A)
 Determination of the distribution rate constant (α) and
the coefficient (A)
 Method of residuals: The
difference between
measured concentrations
and those obtained by
extrapolation of the post-
distribution line is plotted
vs time
1. Determine α from the
graph by using the slope
2. The y-axis intercept of
the extrapolated line is A
Volume of distribution of the central
compartment (VC)
 Volume of distribution of the central
compartment (VC). This is a proportionality
constant that relates the amount of drug
and the plasma concentration immediately
(i.e. at t=0) following the administration of
a drug. (Cp0= Dose/Vc) -------(Cp0 = A+B)
Vc=
Determination of micro rate constants: the inter-
compartmental rate constants (K21 and K12) and
the pure elimination rate constant (K10)
αβ
K1 = K 10 
K 21
K21= Aβ  Bα
K 21 
(A  B)

K12 = + −( + )
Volume of distribution during the
terminal phase (Vb or Vβ)
 This is a proportionality constant that
relates the plasma concentration and the
amount of drug remaining in the body at a
time following the attainment of distribution
equilibrium, or at a time on the terminal
linear portion of the plasma concentration
time data. .
V = =
Volume of distribution at steady
state (Vss)
 This is a proportionality constant that relates the
plasma concentration and the amount of drug
remaining in the body at a time, following the
attainment of practical steady state. This volume
of distribution is independent of elimination
parameters such as K10 or drug clearance.
Xss  ( K 21  K 12 ) 
Vss     Vc
Css  K 21 

Vss= ( + )
The area under the plasma
concentration-time curve (AUC)
 Model independent: Trapezoid method
 Model dependent:

AUC= +
Total Body Clearance, CLT

 The CLT is determined from the dose and

the AUC similar to the one-compartment
pharmacokinetic model:
 TBC = Dose/ AUC
 TBC = .
Problem
 After administration of a single IV bolus dose of 75 mg of
a drug to a healthy volunteer, the pharmacokinetics of
this drug followed the two-compartment model. The
following parameters were obtained:

A = 4.62mg/L B = 0.64 mg/L

α = 8.94 h−1 β = 0.19 h−1

 How to solve
A , α, B, β ‫( ﺩﻭﺭ ﻋﻠﻲ‬A > B) & (α > β)
 t1/2α, t1/2β
 AUC, and CLT.
 Vc
 K10, k21, k12
 Vβ, Vss
Answer
 Calculate t1/2α, t1/2β, k12, k21, k10, Vc, Vdβ, Vdss,
AUC, and CLT.
Cp = Ae−αt + Be−βt
 Cp (mg/L)= 4.62 e-8.94t + 0.64 e-0.19t
 t1/2α= 0.693/α=0.693/ 8.94 = 0.0775 h
 t1/2β = 0.693/ β = 0.693/0.19 =3.65 h

 AUC= +
 AUC = 4.62/8.94 + 0.64/0.19 = 3.8 mg.h/L
Answer
 TBC = Dose/ AUC
 CLT= 75/ 3.8 = 19.3 L/h

 Vc=
 Vc= 75/ (4.62+.64) =14.26 L
 k10= TBC/Vc = 19.3/14.2 = 1.353 h-1

 K21= = 8.94 × 0.19/1.35 = 1.255 h-1

 k12= + −( + )= (8.94 +
0.19) – (1.25+1.35) = 6.52 h-1
 .
 V = =
 Vdβ= 19.3/0.19 = 101.6 L
 Vss= ( + )
 Vdss = 14.25 (1+6.53/1.25) =88.3 L
 What will be the amount of drug remaining in the
body after 8 h?
 Cp(mg/L)= 4.62 e-8.94t + 0.64 e-0.19t
 After 8 hrs. Cp (mg/L)= 4.62 e-8.94(8) + 0.64 e-0.19(8) =
0.139997 mg/L
Amount = conc. x volume (which volume?? Vdβ)
 Amount = 0.13997 x 101.6 = 14.2 mg
 C- What will be the plasma concentration when 90%
of the administered dose is eliminated?
 90 % of the dose is eliminated means that 10 % is still in
the body
 10 % of the dose = 10 × = 7.5 mg
.
 Cp = = 0.0738 mg/L
.

 D- Which of the pharmacokinetic parameters above

mg will change with the increase in the dose to 150?
 A, B, (CP0) & AUC. The rest remain constant.
 The equation will be: Cp (mg/L)= 9.24 e-8.94t + 1.28 e-0.19t
Example 2
 After a single IV bolus dose of 1000 mg of an
antiarrhythmic drug, the following concentrations
were obtained:
Time (hr) Concentration (mg/l)
0.2 120
0.5 84
1 53
2 29
4 18
6 15
8 12.5
12 8.8
Using the method of residual, calculate the following
parameters: αt1/2, β t1/2, k1,k2, k3, Vc, vd β, vdss, AUC
and CLT
 Plot the concentration versus time on a semilog scale.
 Identify the best line that represents the drug elimination
process.
 The y-intercept is equal to B. The hybrid elimination rate
constant (β) and β-half-life can be determined from the line.
 Calculate the residuals from the difference between the
plasma drug concentration and the values on the extrapolated
line during the distribution phase.
 Plot the residuals versus time, and draw the best line that
goes through the points.
 The y-intercept of this line is equal to A. The hybrid
distribution rate constant α and α-half-life can be determined
from this line.
Application of the method of residuals in
solving the example.
Answer
 A = 120 mg/L
 B = 25 mg/L
 α = 1.38 hr-1 tα1/2= 0.5 h
 β= 0.078 hr-1 tβ1/2= 8 hr
 AUC= + = + = 374.4 mg.hr/L
.!" . "
 TBC = Dose/ AUC = 1000/374.4= 2.67 L/h
 Vc= D/(A+B) = 1000/(120+25)=6.9 L
Answer
 k10= TBC/Vc = 2.67/6.7 = 0.387 h-1
 K21= = 1.38 × 0.087/0.387 = 0.310 h-1
 k12= + −( + )= (1.38+
0.087) – (0.310+0.387) = 0.77 h-1
. .#$
 V = = = = 30.7 L
. %$

 Vss= ( + )
 Vdss = 6.7 (1+0.77/0.310) =88.3 L
What will be the amount of drug remaining in
the body after 15 hours?

 Cp = Ae−αt + Be−βt
 Cp(mg/L)= 120 e-1.38* 15 + 25 e-0.087*15= 6.87 mg/L
 Amount of the drug in the body during the
elimination phase = Cp × Vdβ
 Amount15 h = Cp15 h × Vdβ = 6.78 mg/L
× 30.7 L = 208 mg
 Problem 1
 After the administration of a single IV bolus dose of
100 mg lidocaine, the plasma conc-time profile can
be described from the following equation :
Cp(mg/l)= 2.6 e-5t + 0.52 e-0.4t

 Calculate t1/2α, t1/2β, k12, k21, k10, Vc, Vdβ, Vdss,

AUC, and CLT.
 Calculate the amount of lidocaine remaining in the
body after 4 hours
 What will be the plasma lidocaine concentration
when 90 % of the dose is eliminated
 Problem 2
 After an iv bolus dose of 250 mg acyclovir, the
plasma conc-time profile can be expressed by
the following expression:
Cp(mg/L) = 22 e -2t + 6 e 0.23t
 Which of the PK parameters will change when
a dose of 500 acyclovir is administered? And
what will be the new equation?
 Two Compartment Extravascular
K21
absorption Peripheral
Central
Xa compartment compartment
X1 K12 X2
Ka

K10
Oral dose

elimination

dX 1
 K a X a  K 21 X 2  K12 X 1  K10 X 1
dt
dX 2
 K12 X 1  K 21 X 2
dt
Two Compartment Extravascular
Two Compartment Extravascular
 If the drug is rapidly absorbed, the decline in the plasma
concentration–time profile after the end of the absorption
phase will be biexponential, reflecting the distribution
and the elimination phases.

 However, if the drug absorption is slow, the plasma drug

concentration–time profile after oral administration of
drugs that follow two-compartment pharmacokinetic
model can be described by a triexponential equation
that represents the absorption, distribution, and
elimination processes.
A schematic representation of Three-compartment models
consisting of a central and a peripheral compartments.

Deep peripheral
X3

k31 k13
k21
Central Shallow
IV dose compartment Peripheral
(X1) compartment
k12 (X2)
k10

elimination
t  t t
Triexponential Equation: C1  Ae  Be  Ce
Metabolites and
urinary excretion
kinetics
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Outlines
 Metabolite pharmacokinetics
 Renal excretion PK of drugs
 Methods to compute PK parameters
from urinary data
 Determination of the Drug
Bioavailability from the Cumulative
Amount Excreted in Urine
Drug Metabolism
 Drug metabolism, also referred to as drug
biotransformation or drug detoxification, usually
involves enzymatic modification of the chemical
structure of a drug to form one or more
metabolites

 This modification of the drug chemical structure

causes change (increase or decrease) in the
pharmacological and adverse effects of the
drugs.
Drug Metabolism
 The metabolites are usually more polar than
their parent drugs and are excreted rapidly from
the body by the different excretion mechanisms.
 However, there are exceptions to this general
rule where the metabolite half-life is longer than
that of the parent drug.
 Drug metabolism is usually mediated by
specialized enzyme systems that can be
induced or inhibited resulting in modification of
the rate of the drug metabolic process.
Classification of the Metabolic
Reactions:
 Phase I Metabolic Reactions:
 These metabolic reactions are also known as
functionalization reactions or non-synthetic reactions.
 They involve the introduction of polar function groups
such as hydroxyl group, primary amines, carboxylic
acids, etc., to form more polar metabolites.
 The most common phase I reactions include oxidation,
reduction, and hydrolysis.
 These oxidation reactions are mediated mainly by the
cytochrome P450 (CYP450) monooxygenase enzyme
system in addition to other enzyme systems.
Classification of the Metabolic
Reactions:
 Phase II Metabolic Reactions
 These metabolic reactions are also known as
conjugation reactions or synthetic reactions.
 Phase II reactions usually involve formation of
conjugates between the drug and other compounds such
as glucuronic acid, glutathione, amino acids, and others.

 The products of phase II metabolic reactions have

increased molecular weight and are usually inactive.
Cytochrome P450
 CYP450 is a superfamily of metabolizing enzymes that
are responsible for approximately 75% of the total drug
metabolism in humans.
 It contains heme cofactors, so it is considered a
hemoprotein.
CYP 3 A 4 (Nomenclature)
 CYP: GENE for mammalian cytochrome
 3: family (> 40% identical in amino acid sequence)
 A: subfamily (> 70% identical in amino acid sequence)
 4: specific enzyme
Cytochrome P450
 The CYP metabolizing enzymes are present in many
organs including the liver, kidney, lung, gastrointestinal
tract, brain, nasal mucosa, and skin.

 However, the special importance of the role of hepatic

CYP enzymes in drug metabolism arises from the
existence of large amount of enzymes in the liver and
the high hepatic blood flow, which exposes large amount
of the drug in the systemic circulation to the hepatic CYP
enzymes, and also the contribution of the hepatic drug
metabolism to the pre-systemic metabolism of orally
administered drugs.
Metabolite pharmacokinetics
 Drugs can be metabolized through different metabolic
pathways to one or more metabolites, and more than
one metabolite can be detected simultaneously in the
body.
 Some drugs are metabolized to different metabolites
through parallel metabolic pathways. This means that
the different metabolites are formed from the parent
drug, and the formed metabolites are then eliminated
from the body (parallel metabolism).
 In some other drugs, the formed metabolite is further
metabolized to another metabolite, which is then
excreted from the body (sequential metabolism).
Metabolite pharmacokinetics
Metabolite pharmacokinetics
 After drug administration, the metabolite formed is a
new chemical entity that has pharmacokinetic
behavior different from that of the parent drug.
 The elimination rate constant, half-life, volume of
distribution, clearance, and area under the curve for
the metabolite are different from the parameters of
the parent drug.
 So the plasma concentration–time profile for the
drug and the metabolite are usually different
because of the difference in the pharmacokinetic
parameters for the drug and metabolite.
Metabolite pharmacokinetics
 Renal and Non-renal elimination
pathways
Renal drug elimination
(Drug appear
KR unchanged in the urine)

Dose X

KNR Non-Renal drug

elimination (e.g. hepatic
metabolism, Lung,
biliary)
CLT = CLR + CLM + CLL + CLB
Urinary Excretion:
 This means that the first-order elimination
rate constant for the overall elimination
process is the sum of the rate constants
for the different elimination pathways.
k = ke + k m + kl + kb
TBC = k.Vd = ke.Vd + k m.Vd + kl .Vd +
kb.Vd
So if the drug in excreted in urine only
Ke= TBC/Vd = renal clearance/Vd
Renal excretion of drugs
 The renal excretory function starts with the
filtration of the blood reaching the glomeruli,
which occurs normally at a rate of 120 mL/min.
 The three processes involved in the renal
excretion of drugs are the glomerular filtration
(GF) (small molecules only), active tubular
secretion, and tubular reabsorption.

Renal excretion rate = Rate of filtration + Rate of active

secretion - Rate of reabsorption
Renal excretion of drugs
 If the renal clearance equal zero, this mean that
the drug is completely metabolized.
 If the renal clearance equal 120 ml/min, this
mean that the drug is completely excreted by
GF.
 If the renal clearance more than 120 ml/min, this
means that the drug is excreted by GF & Active
secretion.
 If the renal clearance less than 120 ml/min, this
means that some of the drug is reabsorbed.
Methods to compute
PK parameters from urinary data
1. the ‘‘amount remaining to be excreted’’
method (ARE); also known as the sigma-
minus method

2. The rate of excretion method.

Determination of the renal excretion rate

 Consider a drug that is eliminated by first-order

processes, including renal excretion. The renal
excretion rate of the drug at any time is equal to
=Ke A =
 where
 Ae is the amount of the drug excreted in urine
 Ke is the first-order renal excretion rate constant
 A is the amount of the drug in the body
Determination of the renal excretion rate

 To construct the drug renal excretion rate versus

time plot, the experimentally determined renal
excretion rate for the drug during each urine
collection interval is plotted against the time
corresponding to the middle of the urine
collection interval (tmid).
 This is because the calculated drug renal
excretion rate represents the average rate of
renal drug excretion during the urine collection
interval.
Determination of the renal
 Therefore,
 = = . .
 here At-mid is the amount of drug in the body at the
midpoint of the urine collection interval, which is
approximately equal to the average amount of the drug
during the urine collection interval.

Therefore,
/
= . =
Determination of the renal clearance
 Cp tmid is the drug plasma concentration
at the midpoint of the urine collection
interval.

 This means that the drug renal clearance

(CLR) can be determined by collecting
urine over a certain interval and also
obtaining a plasma sample at the middle
of the urine collection interval
 /
= . =

This image cannot currently be display ed.

Determination of the renal excretion rate
 The renal excretion rate versus time profile is
parallel to the blood drug amount-time profile
and the blood drug concentration–time profile
after a single IV administration when the drug
elimination follows first-order kinetics
 Since the drug renal excretion rate at any time is
the product of ke and the amount of the drug in
the body, the drug renal excretion rate–time
profile is always parallel to the blooddrug
amount-time profile and drug concentration–time
profile.
 = = . .
This image cannot currently be display ed.

rate (μg/h)
excretion
Renal
Determination of the renal excretion rate
 Slope of the drug renal excretion rate versus
time plot on the semilog scale is equal to
−k/2.303 and the y-intercept is equal to ke Dose.

 The elimination rate constant, k, can be

determined from the slope of the plot, the
elimination half-life can be calculated from k or
estimated graphically by determining the time
required for any value on the line to decrease by
50%, and ke can be determined from the y-
intercept.
Cumulative amount of the drug excreted
in urine
 The drug renal excretion rate–time profile can be
described by following Equation.
 = . = . . !

 Where AO: the total amount of the drug in the

body at time zero.
 The total amount of the drug excreted in urine is
determined by integrating this equation and
substituting time by infinity:
 Upon integration,
$%
Ae = &'(1 − % !+, )
$
 At time ∞
$% $%
Ae ∞ = &' = /'0%
$ $
where Ae ∞ is the total amount of the drug excreted in urine
when all the drug is eliminated from the body.
Therefore
. 1
=
234
. . ∞ ∞
= . = =
234 5 678 − ∞
Determination of the pharmacokinetic
parameters from the renal excretion rate data
 Elimination Rate Constant and Half-Life:
 Renal Excretion Rate Constant:
The fraction of dose excreted unchanged in urine
after IV administration, f and k, are known (f =
ke/k) or from the y-intercept (ke*D).
 Volume of Distribution: CLR = keVd
 Renal Clearance:
CLR = keVd OR CLR = Ae∞/AUC OR f = CLR/CLT
Determination of the Drug Bioavailability from
the Cumulative Amount Excreted in Urine
 Fraction of Dose Excreted Unchanged in
Urine: ke/k, CLR/CLT, or Ae∞/FDose.

 F absolute =(Ae ∞ (oral) )/(Ae ∞ (iv))

 F relative =(Ae ∞ (test) )/(Ae ∞ (reference))

 Example
 After an IV injection of 500 mg of a new drug to a patient, the
following data were obtained:
Collection Urine Urine
Interval (h) Volume Concentration Cpt-mid

(mL) (mg/mL) (mg/L)

0–2 119 0.60 22.3
2–4 81 0.70 17.7
4–8 160 0.50 12.5
8–12 220 0.23 7.88
12–18 284 0.15 4.42
18–24 212 0.10 2.21
Estimate the biological half-life of this drug in this patient using the urinary excretion
data.
Estimate the renal clearance of this drug in this patient & Calculate TBC
Calculate the fraction of the administered dose excreted unchanged in the urine from the
available data.
Assume that the unexcreted portion of drug is metabolized determine the metabolic rate
constant.
Estimate how much drug is in the body 5 days after the dose was administered.
The rate method (Example)
Time
Volume Concentration
interval
(mL) (mg/mL)
(h)

0–2 119 0.60

2–4 81 0.70

4–8 160 0.50

8–12 220 0.23

12–18 284 0.15

18–24 212 0.10

The rate method:
1- Calculate amount of drug eliminated
Time Drug amount in
Volume Concentration
interval the urine Amount = volume*conc
(mL) (mg/mL)
(h) (mg)

0–2 119 0.60 71.4

2–4 81 0.70 56.7

4–8 160 0.50 80.0

8–12 220 0.23 50.6

12–18 284 0.15 42.6

18–24 212 0.10 21.2

The rate method:
2- Calculate the change in time
Time Drug amount in
Volume Concentration Δt
interval the urine
(mL) (mg/mL) (hr)
(h) (mg)

0–2 119 0.60 71.4 2

2–4 81 0.70 56.7 2

4–8 160 0.50 80.0 4

8–12 220 0.23 50.6 4

12–18 284 0.15 42.6 6

18–24 212 0.10 21.2 6

 The rate method:
3- Calculate the rate of urinary excretion This image cannot currently be display ed.

Time Drug amount in

Volume Concentration Δt
interval the urine
(mL) (mg/mL) (hr)
(h) (mg)

0–2 119 0.60 71.4 2 35.7

2–4 81 0.70 56.7 2 28.35

4–8 160 0.50 80.0 4 20.00

8–12 220 0.23 50.6 4 12.65

12–18 284 0.15 42.6 6 7.10

18–24 212 0.10 21.2 6 3.53

 The rate method:
3- Calculate the rate of urinary excretion This image cannot currently be display ed.

Time Drug t-mid

Concentrati Cpt-mid
Volume amount in Δt
on (hr)
interval (mL) the urine (hr) (mg/L)
(mg/mL)
(h) (mg)

0–2 119 0.60 71.4 2 35.7 22.3 1

2–4 81 0.70 56.7 2 28.35 17.7 3

4–8 160 0.50 80.0 4 20.00 12.5 6

8–12 220 0.23 50.6 4 12.65 7.88 12

12–18 284 0.15 42.6 6 7.10 4.42 15

18–24 212 0.10 21.2 6 3.53 2.21 21

The half-life can be estimated from the renal excretion rate
versus time plot as in Figure.
The half-life is = 6 h, k = 0.1155 h−1. The elimination rate
constant can also be determined from the slope of the line.
The CLR can be estimated from the slope of the renal
excretion rate versus plasma concentration plot. The renal
clearance = 1.6 L/h
Calculate the fraction of the administered dose
excreted unchanged in the urine from the available
data.
 The fraction excreted unchanged in urine
can be calculated from the ratio of the
(ke/k) or (CLR/CLT).

 y-intercept = ke Dose = k"e 500mg =

40mg/h So, ke = 0.08h−1
 f = Ke /k = 0.08/0.1155= 0.69
 TBC = CLR/f = 1.6 / 0.69 = 2.32 L/ hr
Answer
 Assume that the unexcreted portion of drug is
metabolized determine the metabolic rate
constant.
 K = ke + km
 Km = k – ke = 0.1155- 0.08 = 0.0355 hr-1
 Estimate how much drug is in the body 5
days after the dose was administered.
A = Ao . e –Kt
A = 500 . e –0.1155 ×5
 Example
 After an IV injection of 8 mg/kg of a new drug in 24 kg,
10 years patient, the following data were obtained:
Collection Urine Urine
Interval Volume Concentration
(days) (mL) (mg/L)
0–1 600 43.3
1–2 450 46.4
2–4 1340 23.6
4–6 1420 14.4
8–10 1280 7.34
12–14 1300 3.38
Estimate the biological half-life of this drug in this patient using the urinary excretion
data.
Estimate the renal excretion rate constant.
If the initial drug conc. In plasma was 9.2 mg/L, what is the renal clearance?
The rate method (Example)

Time
Volume Concentration
interval
(mL) (mg/L)
(h)
0–1 0.6 43.3
1–2 0.45 46.4
2–4 1.34 23.6
4–6 1.42 14.4
8–10 1.28 7.34
12–14 1.30 3.38
The rate method:
1- Calculate amount of drug eliminated

Amount = volume*conc

Time Drug amount in

Volume Concentration
interval the urine
(L) (mg/L)
(h) (mg)
0–1 0.6 43.3 25.9
1–2 0.45 46.4 20.8
2–4 1.34 23.6 15.8
4–6 1.42 14.4 10.2
8–10 1.28 7.34 4.6
12–14 1.30 3.38 2.1
The rate method:
2- Calculate the change in time

Time Drug amount in

Volume Concentration Δt
interval the urine
(L) (mg/L) (hr)
(h) (mg)
0–1 0.6 43.3 25.9 1
1–2 0.45 46.4 20.8 1
2–4 1.34 23.6 15.8 2
4–6 1.42 14.4 10.2 2
8–10 1.28 7.34 4.6 2
12–14 1.30 3.38 2.1 2
The half-life can be estimated from the renal excretion rate
versus time plot as in Figure. The half-life is = 3.3 day

This image cannot currently be display ed.

Answer
 Estimate Ke
 y-intercept = ke Dose = k"e (8 * 24) = 29 mg/h
So, ke = 0.15 h−1
 If the initial drug conc. In plasma was 9.2
mg/L, what is the renal clearance?
 Cpo= 9.2 mg/L, Vd = D/Cpo=(8 *24)/9=20.86
L
 CLR = keVd = 0.15 * 20.86 = 3.15 L/Day
Example
 If a drug was administered in a dose of 1
gm and the total amount excreted by the
kidney was 910 mg & the renal clearance
was 4.5 L/hr. Calculate the TBC?
. . 9: .
 = 1
= 1
234 234
 TBC = 4.5*1000/910 = 4.94 L/hr
 Practical 7.1
 A patient received a single 1000 mg IV dose of an antibiotic. Urine and plasma
samples were collected and the following results were obtained:

Collection Urine
Urine Volume Cpt-mid
Interval (h) Concentration
(mL) (ug/mL) (ug/mL)
0–1 67 2.1 Not determined
1–2 70 1.01 Not determined
2–4 100 0.50 0.5 ug/ml at time 3
4–8 250 0.05 Not determined

Calculate the average renal execretion rate of the drug during the first urine collection
interval (0-1 hr).
Calculate the average renal execration rate of the drug during the third urine collection
interval (2-4 hr).
Calculate the renal clearance of this drug in this patient.
The half life of this drug is 1 hr. what is the elimination rate constant of this drug?
The slope of renal excretion rate vs time plot on a semilog graph paper?
The rate method (Example)

Time
Volume Concentration
interval
(mL) (ug/mL)
(h)

0–1 67 2.1
1–2 70 1.01
2–4 100 0.50
4–8 250 0.05
The rate method:
1- Calculate amount of drug eliminated

Amount = volume*conc

Time Drug amount in

Volume Concentration
interval the urine
(mL) (ug/mL)
(h) (ug)
0–1 67 2.1 140.7
1–2 70 1.01 70.7
2–4 100 0.50 50
4–8 250 0.05 12.5
The rate method:
2- Calculate the change in time

Time Drug amount in

Volume Concentration Δt
interval the urine
(mL) (ug/mL) (hr)
(h) (ug)

0–1 67 2.1 140.7 1

1–2 70 1.01 70.7 1
2–4 100 0.50 50 2
4–8 250 0.05 12.5 4
 The rate method:
3- Calculate the rate of urinary excretion

This image cannot currently be display ed.

Time Drug amount in

Volume Concentration Δt
interval the urine
(mL) (ug/mL) (hr)
(h) (ug)
0–1 67 2.1 140.7 1 140.7
1–2 70 1.01 70.7 1 70.7
2–4 100 0.50 50 2 25
4–8 250 0.05 12.5 4 3.125
 The rate method:
3- Calculate the rate of urinary excretion

This image cannot currently be display ed.

Time Drug t-mid

Concentrati Cpt-mid
Volume amount in Δt
on (hr)
interval (mL) the urine (hr) (ug/mL)
(ug/mL)
(h) (ug)
0–1 67 2.1 140.7 1 140.7 ND 0.5
1–2 70 1.01 70.7 1 70.7 ND 1.5
2–4 100 0.50 50 2 25 0.5 3
4–8 250 0.05 12.5 4 3.125 ND 6
Calculate the renal clearance of this drug in
this patient.

= = . .

 Cl R= Ke.Vd = 3; < 3 /
=25/0.5 = 50 mL/hr
Answer
 The half life of this drug is 1 hr. what is the
elimination rate constant of this drug?
 T1/2= 1hr k= 0.693/1= 0.693 hr -1

 The slope of renal excretion rate vs time

plot on a semilog graph paper?
 Slope = - k/ 2.303 = 0.693/2.303 = - 0.3 hr -1
 Problem 7.2 (Practice problem)
 After IV injection of 10 mg of a new drug to a patient, the following
data were obtained:
Collection Urine Urine
Interval (h) Volume Concentration Cpt-mid

(mL) (ug/mL) (ug/L)

0–1 1250 1.8 16
1–2 1500 0.984 10.4
2–3 1750 0.544 6.8
3–4 1380 0.488 4.4
4–5 1630 0.248 2.9
5–7 3130 0.136 1.5
1- Using a graphical method, estimate the biological half-life of this drug in this patient.
2- Calculate the renal clearance and total body clearance of this drug in this patient.
3- Calculate the fraction of the administered dose execrated unchanged in the urine from
the above data.
4- Estimate how much drug in the body 5 days after the dose was administered.
5- Assuming that the unexcreted portion of this drug is metabolized, determine its
metabolic rate constant (km) in this patient.
General comment on rate method

 The method tends to give overestimate of

intercept.
 The overestimation can be minimized by
collecting urine samples more frequently
(which is not always easy from practical
consideration)
General comments on the use of urinary
data in PK analysis
 Urine collection is a non-invasive technique
 It is, perhaps, a more convenient method of
sample collection, and sample size is generally
not a problem. The sampling time, however,
reflects drug in urine collected over a period of
time, rather than a drug concentration at a
discrete time
 Urinary data allows direct measurement of
bioavailability, both absolute and relative,
without the need of fitting the data to a
mathematical model.
 Nonlinear
pharmacokinetics
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Outlines
 Linear pharmacokinetics
 Nonlinear pharmacokinetics
 Example of Nonlinear PK (Phenytoin)
 M-M equation
 Orbit graph method
 Direct linear plot
 Linear transformation method
Linear Pk
 Pharmacokinetic parameters, such as elimination half life
(t1/2), the elimination rate constant (K), the apparent
volume of distribution (V), and the systemic clearance
(Cl) of most drugs are not expected to change when
different doses are administered and/or when the drug is
administered via different routes as a single dose or
multiple doses
 The kinetics of these drugs is described as linear, or
dose-independent, pharmacokinetics and is
characterized by the first-order process
 The term linear simply means that plasma concentration
at a given time at steady state and the area under the
plasma concentration versus time curve (AUC) will both
be directly proportional to the dose administered

3
Linear Pk

4
Linear Pk
 In this situation, steady-state serum
concentrations increase or decrease
proportionally with dose.

 Therefore, if a patient has a steady-state drug

concentration of 10 μg/mL at a dosage rate of
100 mg/h, the steady-state serum concentration
will increase to 15 μg/mL if the dosage rate is
increased to 150 mg/h (e.g., a 50% increase in
dose yields a 50% increase in steady-state
concentration).

5
Nonlinear Pk
 For drugs that exhibit nonlinear or dose
dependent kinetics or concentration dependent,
the fundamental pharmacokinetic parameters such
as clearance, the apparent volume of distribution,
and the elimination half life may vary depending on
the administered dose.

 For these drugs, therefore, the relationship between

the AUC or the plasma concentration at a given time
at steady state and the administered dose is not
linear (not directly proportional)

 Most drugs follow linear kinetics at therapeutic doses.

However, Some drugs follow non linear kinetics
including phenytoin.
6
Nonlinear Pk

7
Nonlinear Pk
Administration of
different doses of
drugs with nonlinear
kinetics may not
result in parallel
plasma
concentration
versus time profiles
expected for drugs
with linear
pharmacokinetics

8
9
Nonlinear Pk Causes
 This is because one or more of the kinetic processes
(absorption, distribution and/or elimination) of the drug may
be occurring via a mechanism other than simple first-order
kinetics.
 Saturable absorption: For example, the extent of
absorption of amoxicillin decreases with an increase in
dose
 Saturable binding: plasma protein binding of
disopyramide is saturable at the therapeutic concentration,
the fraction of disopyramide bound varies between 35% at
high doses & 95% at low doses. This means that small
increase in doses result in disproportionally increase in the
effect

10
Nonlinear Pk Causes
 Saturable Active secretion: As for nonlinearity in
renal excretion, it has been shown that the
antibacterial agent dicloxacillin has saturable
active secretion in the kidneys, resulting in a
decrease in renal clearance as dose is increased

 Saturable metabolism: Both phenytoin and

ethanol have saturable metabolism, which means
that an increase in dose results in a decrease in
hepatic clearance and a more than proportional
increase in AUC
11
Nonlinear Pk
 When steady-state concentrations increase less than
expected after a dosage increase, there are two typical
explanations:

 Some drugs, such as valproic acid and disopyramide,

saturate plasma protein binding sites so that as the
dosage is increased, steady-state serum concentrations
increase less than expected till complete saturation.

 Other drugs, such as carbamazepine, increase their own

rate of metabolism from the body as dose is increased
so steady-state serum concentrations increase less than
anticipated. This process is known as autoinduction of
drug metabolism.
12
Nonlinear PK
 In either case, the relationship between steady-state
concentration and dose for drugs that follow nonlinear
pharmacokinetics is associated with significant
intersubject variability.
 Drugs that exhibit nonlinear pharmacokinetics are
oftentimes very difficult to dose correctly.
 Theoretically, all metabolic pathways can be saturated
at very high drug concentration. However, saturable
drug metabolism is of clinical significance when
saturation occurs after administration of therapeutic
doses of the drug.
 Steady-state serum concentrations/dose plots for
medications are determined in humans early during the
drug development process.
13
 Difference between linear & nonlinear PK:

Linear PK Nonlinear PK
( first order kinetic) (zero order kinetic)
1-Known as dose-independent or 1-Known as dose-dependent or
concentration-independent PK. concentration-dependent PK.
2-The absorption, distribution and 2-At least one of the PK processes
elimination of the drug follow first-order (absorption, distribution or elimination)
kinetics is saturable (zero order kinetic).
3-The pharmacokinetic parameters such 3-The pharmacokinetic parameters
as the half-life, total body clearance and such as the half-life, volume of
volume of distribution are constant and distribution, total body clearance are
do not depend on the drug conc conc-dependant
4-The change in drug dose results in 4-The change in drug dose results in
proportional change in the drug more than proportional or less than
concentration. proportional change in the drug conc.
14
 Difference between linear & nonlinear PK:

Linear PK ( first order Nonlinear PK (zero

kinetic) order kinetic)
Proportional dose response relationship disproportional dose response
(Cp, AUC) relationship (unpredictable)
Increase in dose resulted in more than
proportional increase in Cp & AUC
Constant proportion (fraction) eliminated Constant amount eliminated per unit
per unit time time
T1/2 & Cl (constant) ( useful ) T1/2 & Cl are variable ( not useful )

Superimposable Not superimposable

Terminal parts of plasma conc. Curve Terminal parts of plasma conc. Curve
after oral & iv are superimposed after oral & iv are not parallel or
superimposed
15
 Nonlinearity in metabolism
Capacity-limited metabolism
 Capacity-limited metabolism is also called
saturable metabolism, Michaelis–Menten
kinetics
 Nonlinearity in metabolism, is one of the
most common sources of nonlinearity
 Phenytoin, ethanol, and salicylic acid
follow Michaelis-Menten pharmacokinetics

16
 Michaelis–Menten kinetics
 Michaelis-Menten kinetics model that describe
saturable enzyme system
 Used to predict Cp resulting from administration of
drug with saturable metabolism where a drug at low
concentration is cleared by first-order kinetics and at
high concentrations by zero order kinetics
 Conditions that alter M-M parameters
 Enzyme Induction or inhibition (Vm)
 Hepatic disease

17
Michaelis- Menten kinetics

Vm is the maximum metabolic rate (unit: amount/time)

Km :Substrate concentration at 50% Vm ( mg / L ), the Michaelis–Menten
constant (unit: same as the concentration [amount/volume]),

18
Michaelis- Menten kinetics

a drug at low concentration is cleared by first-order

kinetics and at high concentrations by zero order kinetics

19
 Michaelis- Menten kinetics
 The rate of metabolism, or the rate of elimination if metabolism is
the only pathway of elimination, is defined by the Michaelis–
Menten equation:
∗
R( )=
 where R is the rate of drug administration or the metabolic rate;

( )= =DD.S
 Vm is the maximum metabolic rate (unit: amount/time)
 Km :Substrate concentration at 50% Vm ( mg / L ), the Michaelis–
Menten constant (unit: same as the concentration [amount/volume]),
and Css plasma conc at steady state .
. !
t1/2= ( + ) TBC =

20
 Phenytoin & its key pharmacokinetic
parameters
Phenytoin is antiepileptic drug that follow
EXCLUSIVE non-linear kinetic
Therapeutic concentration 20- 10mg / L
F ( bioavailability ) 1.0
S ( salt form ) 0.92
Vd 0.7 L/ kg
Cl ( clearance ), t1/2 Dose dependant
Vm 7mg / kg / day
Km 4mg /L (average) Constant
PPB %95-90
Plasma concentration below 5 mg/L not effective 21
 Phenytoin
Phenytoin side effect is Other long term side effect
concentration dependent

 20 – 30 mg/L (Nystgmus)  Acne, hirsutism, folate

 > 30 m/L (Ataxia) deficiency, neuropathy,
 >40 m/L (mental capacity gingival hyperplasia
diminished)

22
 Phenytoin dosage forms

Phenytoin Na
Phenytoin acid
(s=.92)
Chewable tablet Capsules
Suspension Parenteral solution

N.B:
 Change between different brands should consider
the difference in bioavailability.
 Poor solubility, so it is formulated in microcrystal
form
23
 Rationale for TDM
 Saturable elimination at therapeutic range
 Lack of predictability
 Narrow therapeutic index
 Significant drug interaction
 Large intersubject variability

 Time to take blood sample: 2- 3 days after

intitation, second level in 3- 5 days, if Ok, it
should be monitored everey 3-12 months)
24
 Phenytoin dosing to patient
 Three situations
 Patient 1st visit : no dose, no serum level
 Patient 2nd visit : a dose is present,
serum level determined
 Patient 3rd visit : 2 doses & 2 serum levels

25
 Patient 1st visit : no
individualized data available

26
 Patient 1st visit : no
individualized data available
 Use population date Km= 4 mg/L, Vm=7
mg/kg/day & Vd = 0.7 L/Kg/day
 Mathematically: M-M Equation
#$ (#∗%)*+,)% -**
 R ( ) =
%&' .# %)*+,)% -**
<=
 /012 34 05678791:01738(/;) = ?=DD.S
>

 D/τ= daily dose

27
 Graphically using Orbit graph
method
 The orbit graph is a plot of
Vmax vs. km with
probability contours drawn
on it.
 x-axis is labeled Km & the
extension of the x-axis in
the negative direction
labeled Css.
 The y-axis labeled both
Vmax and dose.
 Dose is plotted as mg/kg/d
of phenytoin.
 This method uses data
previously derived from a
patient population to
construct shapes, orbit
representing 50, 75, 90,95
and 97.5%
Graphically: Orbit graph method
(phenytoin nomogram)

29
Patient 2nd visit : one dose &
one level available

30
 Patient 2nd visit : one dose &
one level available
 Use the given dosing rate & the measured
serum level to calculate Vm Michaelis
Menten equation assume Km = 4
mg / L
#$ (#∗%)*+,)% -**
 R ( )= DD.S =
%&' .# %)*+,)% -**

31
Example 1
S.B. is a 70 kg , 37 Y.O. male with seizure disorde
r that only partially been controlled with 300mg /
day capsules of phenytoin. His plasma phenytoin
conc. has been measured twice over the past
year & both times it was 8 mg / l. Calculate a daily
dose which will achieve a steady state
concentration of 15 mg / l.

32
Answer
 R = 300 mg / day , Cpss = 8 mg/L , S = 0.92 F = 1
#$ (#∗%)*+,)% -**
 R ( )= DD.S =
%&' .# %)*+,)% -**
(#∗@
 300 ∗ 0.92 =
A @
 Vm = ( 12 * 300 * 0.92 )/ 8 = 414 mg / day
AEA ∗EF
 DD ∗ 0.92 = =355 mg/day
A EF

33
Example 2
 B.U. is a 9 Y.O. 30 kg male who has been admitted to
the emergency dep. for treatment of uncontrolled
seizure activity. His friend relates that he has been
taking 180 mg chewable tablet of phenytoin QD for 6
weeks, serum levels of phenytoin was found to be 3 mg
/ l . Assume that this is a steady state level. Calculate
Vmax for this patient.
 In the above case, what is the new dose of phenytoin
required to yield a steady state plasma concentration of
15 mg / l ?

34
Answer
 R =180 mg / day , Cpss = 3 mg/L S =
1.0 F = 1.0
#$ (#∗%)*+,)% -**
 R ( )= DD.S =
%&' .# %)*+,)% -**
(#∗G
 180 ∗ 1 =
A G
 Vm = ( 7 * 180 * 1 ) / 3 = 420 mg / day
AHI∗EF
 DD∗ 1 = = 332 mg / day
A EF

35
Orbit graph
1. On the left side of the x-axis, a steady-state total
phenytoin concentration is plotted.
2. On the y-axis, the phenytoin dosage rate (in mg/kg/d) is
plotted.
3. A straight line is drawn between these two points,
extended into the right sector, and through the orbs
contained in the right sector.
4. If the line intersects more than one orb, the innermost
orb is selected, and the midpoint of the line contained
within that orb is found and marked with a point.
5. The midpoint within the orb and the desired steady-state
phenytoin total concentration (on the left portion of the x-
axis) are connected by a straight line.
Orbit graph
6. The intersection of this line with the y-axis is the new
phenytoin dose required to achieve the new phenytoin
concentration.
7. If a line parallel to the y-axis is drawn down to the x-axis
from the midpoint of the line contained within the orb, an
estimate of Km (in μg/mL) is obtained.
8. Similarly, if a line parallel to the x-axis is drawn to the left
to the y-axis from the midpoint of the line contained
within the orb, an estimate of Vmax (in mg/kg/d) is
obtained.
Example
 TD is a 50-year-old, 75-kg (5 ft 10 in) male with
simple partial seizures who requires therapy with
oral phenytoin. He has normal liver and renal
function. The patient was prescribed 400 mg/d of
extended phenytoin sodium capsules for 1
month, and the steady-state phenytoin total
concentration equals 6.2 μg/mL. The patient is
assessed to be compliant with his dosage
regimen. Suggest an initial phenytoin dosage
regimen designed to achieve a steady-state
phenytoin concentration within the therapeutic
range.
phenytoin dose =
0.92 ⋅ phenytoin sodium dose =
0.92 ⋅ 400 mg/d = 368 mg/d;
368 mg/d / 75 kg = 4.9 mg/kg/d
Patient 3rd visit : two doses &
two levels available

40
 Patient 3rd visit : two doses &
two levels available
Use the two dosing rate & the two
measured serum levels to calculate the new
Vm & Km by Michaelis-Menten equation

#$ (#∗-**
R ( )= DD.S =
%&' .# -**

41
Example 3
 RM is a 32 year old, 80kg male who is being seen in the
Neurology Clinic. Prior to his last visit he had been taking
300mg of Phenytoin daily; however, because his
seizures were poorly controlled and because his plasma
concentration was only 8mg/L, his dose was increased
to 350mg daily. Now he complains of minor CNS side
effects and his reported plasma Phenytoin concentration
is 20mg/L. Renal and hepatic function are normal.
Assume that both of the reported plasma concentrations
represent steady state and that the patient has compiled
with the prescribed dosing regimens. Calculate RM’s
apparent Vm and Km and a new daily dose of Phenytoin
that will result in a steady state level of about 15mg/L.
42
Answer
R1* Km  R1* CSS (1)  Vm * CSS (1)
R 2 * Km  R 2 * CSS (2)  Vm * CSS (2)
R1  300 mg / day, CSS (1)  8 mg / L
R 2  350 mg / day, CSS (2)  20 mg / L
300 * Km  300 * 8  Vm * 8  37.5 * Km  300  Vm (1)
  
350 * Km  350 * 20  Vm * 20  17.5 * Km  350  Vm (2)
Eqn (1)- Eqn(2):

20 * Km  50  0 50
Km   2.5 mg / L
20
Eqn (1):

Vm  37.5 * Km  300  37.5 * 2.5  300  393.75 mg / day

43
 Calculate RM’s a new daily dose of
Phenytoin that will result in a steady state
level of about 15mg/L

VmCSS 393.75 *15

Dosing rate    337.5 mg / day
Km  CSS 2.5  15

44
 Direct Linear Plot
 Direct linear plot is a linear transformation method that is
used to estimate Vmax and Km.
 This method requires knowledge of two different dosing
rates and their corresponding steady-state plasma drug
concentrations.
 The plot is constructed by plotting the dosing rate in the
y-axis and the steady-state drug concentration on the left
side of the x-axis. A line is drawn between each dosing
rate and its corresponding steady-state concentration.
 The two lines for the two dosing rates are extrapolated
until they intersect.
 The x-coordinate of the point of intersection corresponds
to Km, while the y-coordinate of the point of intersection
corresponds to Vmax/F as presented in following Figure.
45
Direct Linear Plot

46
 Example 3
 A 32-year-old, 75 kg female has been taking 200 mg of phenytoin daily.
Because her average phenytoin plasma concentration was only 6 mg/L, her
phenytoin dose was increased to 350 mg/day. The steady-state average
phenytoin concentration was 21 mg/L (Vd of phenytoin is 0.75 L/kg and F =
1).
 a. Using the direct linear plot, calculate the phenytoin Vmax and Km in this
patient.
 b. Calculate the dose required to achieve an average steady-state
phenytoin plasma concentration around 15 mg/L.
 c. Calculate phenytoin half-life & TBC at steady state while the patient was
taking 350 mg/day.
 d. Because of poor seizure control, phenobarbitone (enzyme inducer) was
added to the patient’s medications. After several weeks, phenytoin plasma
concentration was 14 mg/L while taking 360 mg/day phenytoin. Comment
on the decrease in phenytoin plasma concentration.

47
Answer

48
Answer
 From the direct linear plot Vmax = 500 mg/day; Km
9 mg/L
 The dose required to achieve a steady-state
concentration of 15 mg/L can be determined
graphically and mathematically.
 Graphically from Figure, the dose is
approximately 315 mg/day (Approximately 350
mg). Mathematically,
(#∗-** FII∗EF
 Dosing rate= = =312.5 mg/day
.# -** K EF

49
 C- Steady state when the dose was 350
mg/day = 21 mg/L.
. !
 t1/2= ( + )
. ! ( .L M ∗LN )
 t1/2= ( + OP) = 2.18 days
N
N
 TBC = = =16.67 L/Day
OP

 D- Phenobarbitone is an enzyme inducer that

can increase the rate of phenytoin metabolism
(increase Vmax) and decrease its steady-state
concentration.
50
Practical Problem 1
 A 78 kg, 28-year-old man is receiving phenytoin for the treatment of
seizures. When this patient was taking a daily oral dose of 250 mg
phenytoin, his steady-state plasma concentration was 7.2 mg/L.
Because phenytoin plasma concentration was well below the
therapeutic range, the patient’s daily dose was increased to 450 mg
phenytoin, which resulted in a steady-state plasma concentration of
30 mg/L. (Assume that the absolute bioavailability of oral phenytoin
is 100%, and that the volume of distribution of phenytoin is 50 L.)
 a. Graphically calculate the patient’s Vmax and Km.
 b. Calculate phenytoin half-life in this patient at steady state while
taking 450 mg daily.
 c. What is the steady-state concentration that should be achieved if
the dose was 300 mg daily?
 d. What is the daily phenytoin dose that should achieve a steady-
state phenytoin plasma concentration of 20 mg/L in this patient?

51
Answer

a. Vmax = 600 mg/day, Km = 10 mg/L

52
Answer
 b. Calculate phenytoin half-life in this patient at steady
state while taking 450 mg daily.
. !
 t1/2= ( + )
Q
. ! ∗N
 t1/2= (P + ! ) = 2.31 days
 c. What is the steady-state concentration that should be
achieved if the dose was 300 mg daily?
(#∗-**
 Dosing rate=
.# -**
RII∗-**
 300 = =10 mg/L
EI -**
53
Answer
 d. What is the daily phenytoin dose that should achieve a
steady-state phenytoin plasma concentration of 20 mg/L
in this patient?
(#∗-**
 Dosing rate=
.# -**
RII∗HI
 Dosing rate = =400 mg/day
EI HI

54
 Linear Transformation method
 This method is based on a linear transformation of M-M
Equation that relates the dosing rate and the achieved
steady-state drug concentration and includes the
Michaelis-Menten parameters, Vmax and Km:
#$ <= (#∗-**
 R ( ) = =
%&' > .# -**
<= <=
 S6 + T99 = U6 ∗ T99
> >
 Rearrangement and dividing by F Css
X
= Y (#
 = −W6 +
> -** <
55
Linear Transformation method:
 This is a straight-line equation.
 A plot of the dosing rate (D/τ) versus the dosing rate
divided by the average steady-state concentration yields
a straight line with a slope equal to −Km and y-intercept
equal to Vmax/F.
 The parameters Vmax and Km estimated from the slope
and the y-intercept of the plot can be used to calculate
the dosing rate required to achieve a certain Cpss or,
conversely, to calculate the expected Cpss from
administration of a given dosing rate.

56
Linear Transformation method:

57
Practical problem 2
 A 25 kg, 14-year-old female was admitted to the hospital because of
frequent episodes of seizures. She was diagnosed as having epileptic
seizures and she was started on IV phenytoin. She received a loading dose
of 5 mg/kg followed by 80 mg phenytoin IV given every 12 h. At steady
state, the average plasma phenytoin concentration was found to be 8 mg/L.
The phenytoin dose was increased to 100 mg phenytoin IV given every 12
h. At steady state, the plasma phenytoin concentration was 13.3 mg/L.
Because the patient’s condition was stable, the IV phenytoin was replaced
with phenytoin oral suspension, which is known to have 100%
bioavailability. The patient went home with a prescription for 225 mg
phenytoin suspension at bed time every day. (The volume of distribution of
phenytoin is 0.8 L/kg.)
 a. Graphically estimate phenytoin Vmax and Km in this patient.
 b. What is the expected average steady-state phenytoin concentration in
this patient while taking the 225 mg phenytoin suspension at night?
 c. Calculate phenytoin CLT and half-life in this patient while taking the
phenytoin suspension (225 mg phenytoin at bed time) at steady state.

58
Answer
 a. Vmax = 340 mg/day Km = 8.8 mg/L
 b. Cpss = 17.2 mg/L
 c. Half-life = 1.1 day CLT = 13.0 L/day

59
Drug Distribution
&
Protein binding

Dr. Mahmoud Samy

Lecturer of Clinical Pharmacy
 Outlines
 Drug Distribution & Protein binding

 Dosing regimen - Disease state in special

populations
 Dosing Regimens in Renal Dysfunction Patients
Based on Creatinine Clearance
 Dose Adjustment in Hepatic Dysfunction:
 Alteration in Drug Pharmacokinetics in Obese
Patients
Drug Distribution & Protein binding

 The distribution of drugs in the body

depends on their lipophilicity & protein
binding.
 Factors affecting drug distribution:
 A. Rate of distribution
 1- Membrane permeability
 2- Blood perfusion rate

3
 Drug Distribution & Protein binding
 B. Extent of Distribution
 1. Lipid Solubility:
 Very high lipid solubility can result in a drug partitioning into highly vascular lipid-
rich areas. Subsequently these drugs slowly redistribute into body fat where they
may remain for long periods of time.
 2. Effects of pH:
 The rate of movement of a drug out of circulation will depend on its degree of
ionization and therefore its pKa.
 3.Plasma protein binding:
 Extensive plasma protein binding will cause more drug to stay in the
central blood compartment. Therefore drugs which bind strongly to
plasma protein tend to have lower volumes of distribution. (↑ protein
binding = ↓ V)
 Albumin comprises 50 % of the total proteins binds the widest range
of drugs.
 Acidic drugs commonly bind to albumin, while basic drugs often
bind to α1-acid glycoproteins and lipoproteins.
4
 General rules
 Rule 1: Plasma proteins represent silent binding site (depot)
for drugs: the BOUND drug is inactive; the FREE,
UNBOUND drug can leave the blood and act and can be
acted upon. As long as a drug is bound to plasma protein, it
cannot act (as it cannot reach the site of action), it cannot be
eliminated (as it can not reach enzymes and transporters,
and cannot be filtered at the glomeruli).

 Rule 2: Only for extensively bound drugs (>90%) can

changes in the FREE (active) drug fraction be significant.
Drug with intermediate plasma protein binding: Decreased
binding causes insignificant increase in free concentration.

5
 The percentage of protein binding
 The percentage of protein binding of a drug in plasma
can be determined experimentally as follows:
( )×
 % Protein binding =
!

 The fraction of unbound drug in the plasma (Fp) is

determined by the following relationship:
($%&'(%)*))
"# =
+'+,-

6
 Dosing regimen
&
Disease state in special
populations
Dr. Mahmoud Samy
Lecturer of Clinical Pharmacy
Introduction
 The design of a dosing regimen involves selection of the
appropriate dose and dosing interval for each individual
patient.
 Few factors have to be considered before calculating the
dosing regimen:
 Therapeutic Range of the Drug
 Required Onset of Effect
 Drug Product (availability of modified-release products
for the drug of interest)
 Progression of the Patient’s Disease State
 Estimation of the Patient Pharmacokinetic Parameters

8
 Variables that can affect total body clearance
(TBC) within individual
 Changes in eliminating organ function leads to
changes in total body clearance
TBC = Rcl + Mcl + Other organ clearance
 Factors affecting metabolic clearance including:
Age, Genetics, Liver disease, Plasma protein
binding & other drug that induce or inhibit metabolic
enzymes.
 Factors affecting renal clearance including: it is
related to glomerular filtration rate (GFR) which
measured by creatinine clearance.

9
 Effect of age on volume of distribution (Vd):
 In very young infant, hydrophilic drugs have
large Vd as infant has higher proportion of their
body weight as water (80 %)

 In elderly person, hydrophilic drugs have

reduced Vd due to reduced extracellular fluids,
tissue mass and decreased tissue perfusion.

 In older patients, the body fat increased so lipid

soluble drugs have larger Vd and longer t1/2

10
 Effect of age on drug metabolism & renal
function
 Effect of age on drug metabolism
 In neonates ( < 1 months), they have slow metabolic rate
so drugs have longer t1/2
 In Children (3 – 12 y), they have normal metabolic rate
 In elderly ( > 65 y), they have slow metabolic rate so
drugs have longer t1/2

 Effect of age on renal function:

 Average adult value of GFR (120 ml/min)
 Premature infants have 1/10 of normal GFR
 Neonates have 1/2 or 1/4 of normal GFR

11
 The general approach for dose adjustment in renal
dysfunction patients has the following assumptions:
 The kidney dysfunction does not affect the
concentration-effect relationship, that is, the therapeutic
range does not change due to the change in kidney
function (Linear PK).

 The decrease in kidney function results in a proportional

decrease in the rate of renal drug elimination.

 The decrease in kidney function does not affect the

nonrenal drug elimination.

 The decrease in kidney function does not affect drug

absorption or distribution.

12
 General Requirements
 This approach requires knowledge of:
 The average drug dose in patients with normal kidney
function (Normal Dose).

 the kidney function of the patient (KF)

 The fraction of the IV drug dose excreted unchanged in

urine in patient with normal kidney function (F).

 This information can be used to calculate the dose

required for patients with kidney dysfunction to achieve
an average steady-state concentration similar to that
achieved in patients with normal kidney function when
they use the average dose of the drug.
13
 Dose failure
 The fraction of the dose normally excreted unchanged in
the urine, the kidney function, and the average dose
used in patients with normal kidney function can be used
to calculate the dose required in patients with renal
dysfunction as follows:
Dose failure = Dose normal [. (KF −1) +1]
 Also, the half-life in patients with renal dysfunction
patients can be determined from the following
relationship:
: 0/2 ;<=>?@
/0/2 3456789 =
[. BC − 0 + 0]

14
 Fraction (f)
 The fraction of the IV dose excreted unchanged in urine (f) can be
determined from the ratio of the total amount of the drug excreted in
urine and the IV dose or the bioavailable oral dose:
GH
Fraction (f) =
I<JH (KL)
GH
Fraction (f) =
C I<JH (M=?@)
 Also, the fraction excreted unchanged in urine can be determined
from the ratio of the renal excretion rate constant to the elimination
rate constant or the ratio of the renal clearance to the total body
clearance as follows:
BH NOP
Fraction (f) = =
B QRN

15
 Kidney function (KF)
 The initial dose estimation for renally eliminated drugs in
renal dysfunction patients is usually based on the patient’s
creatinine clearance.

 This is because the decrease in kidney function, which is

reflected by the decrease in creatinine clearance, results in
the decrease in renal clearance of the drug.

 The kidney function (KF) is expressed as the fraction

remaining of the normal kidney function and is determined
from the ratio of creatinine clearance in the patient to normal
creatinine clearance:

N=NO .?K@S=H
KF =
N=NO ;<=>?@
16
 Creatinine Clearance from urine collection
 The creatinine clearance can be determined from the
24 h urine collection and calculation of the average
creatinine excretion rate.
 CrCl (in mL/min) = (UCr ⋅ Vurine) / (SCr ⋅ T)
where:
 UCr is the urine creatinine concentration in mg/dL,
 Vurine is the volume of urine collected in mL,
 SCr is the serum creatinine collected at the midpoint of
the urine collection in mg/dL,
 T is the time in minutes of the urine collection.
 Disadvantages: Tedious method, Time consuming,
Affected by diet & muscle mass, Not accurate
17
 Cockroft and Gault method
 The Cockoroft and Gault method can be used to
estimate the creatinine clearance in adults from 18 years
and older with stable serum creatinine.
 Male:
0UV 4W9 X Y95WZ/ ([\)
Creatinine clearance (ml/min) =
]987^ _894/5`5`9 X a2
 Female:
0UV 4W9 X Y95WZ/ ([\)
Creatinine clearance (ml/min) = V. cd X
]987^ _894/5`5`9 X a2

 1 kg = 2.2 pound, for example 132 pound = 60 kg

18
 Problem 8.1
 A patient admitted to the hospital because of acute myocardial
infarction was started on oral antiarrhythmic medication. He was
given 600 mg every 12 h from an oral formulation that is known to
be rapidly absorbed but only 80% bioavailable. At steady state,
the maximum and minimum plasma concentrations were 30 and
10.5 μg/mL, respectively
 a. Calculate mathematically the half-life and the volume of
distribution of this drug in this patient.

 b. The patient suddenly developed acute renal failure and the

kidney function dropped to 30% of its normal value. If the renal
clearance of this drug is 75% of the total body clearance,
recommend an appropriate dose for this patient after developing
the renal failure.

 c. Calculate the maximum and minimum plasma concentration

achieved at steady state from the regimen you recommended in
part (b).
 A) Normal renal function
 Cpmin ss = Cpmax ss e-kτ
efg]9
 Cpmax ss - Cpmin ss =  ln Cpmin ss = ln Cpmax ss - ln e-kτ
hi
V.c X jVV Cpmax ss
 30-10.5 = Ln ( ) = Kτ
hi Cpmin ss
 Vd= 480/19.5= 24.6 L
 Ln (30/10.5)= 12 K
 K= 0.0875 hr-1
 t1/2 = .693/ 0.0875 = 7.9
hrs.
 B) At renal dysfunction
k l m op
 Fraction (f) = = = = 0.75
k nl
lml!t u! m
 KF= = 0.3
lml! mv !
 Dose failure =Dose normal [f(KF-1)+1]
 Dose failure =600mg/12 h [0.75(0.3-1)+1]
 Dose failure =600mg/12 h [0.75(-0.7)+1]
 Dose failure =600mg/12 h [-0.525+1]
 Dose failure =600mg/12 h [ 0.475]
 Dose failure =285 mg/12 h
 B) At renal dysfunction
/ 0/2 `g8^46
 T1/2failure =
[3 (xe 0) y0]
a.z
 T1/2failure = =16.6 hr
V.Uad

 K=0.693/16.6= 0.0416 hr-1

 C) Calculate the maximum and minimum plasma
concentration achieved at steady state from the regimen
you recommended in part (b).

 Regimen 285/12h
CI
|}∞ ^4X =
•€(0 H{B• )
V.cX2cd
 Cpmax ss = = 23.58 mg/l
2U.j(0 9{ .VU0jX 02 )

|}∞ ^5` = |}∞ ^4X . H B•

 Cpmin ss = 23.58e-.0416 x12

 Cpmin ss = 14.2 mg /L
 Problem 8.2
 A patient was admitted to the hospital because of severe pneumonia. An
IV loading dose of an antibiotic followed by IV maintenance doses of 300
mg q12 h were prescribed. The creatinine clearance was 120 mL/min,
which is considered normal for this patient. After 7 days of therapy (300 mg
q12 h), the maximum and minimum plasma concentrations were 38 and
12.5 mg/L, respectively.
 A- Calculate mathematically the half-life and the volume of distribution of
this drug in this patient.
 At steady state (while receiving 300 mg q12 hr) 180 mg of the drug is
excreted unchanged in urine during one dosing interval. What is the renal
clearance of this drug?
 After 15 day of antibiotic therapy, the kidney function of this patient
deteriorated and his creatinine clearance was found to be 40 ml/min. what
is the new half-life of the drug after this change in the patient’s kidney
functions?
 What will be the steady state maximum and minimum plasma
concentrations if this patient continues taking 300mg q12 hr despite the
change in his kidney functions?
 A) Normal renal function
efg]9  Cpmin ss = Cpmax ss e-kτ
 Cpmax ss - Cpmin ss =
hi  ln Cpmin ss = ln Cpmax ss - ln e-kτ
‚VV
 38-12.5 = Cpmax ss
hi
Ln ( ) = Kτ
 Vd= 300/25.5= 11.76 L Cpmin ss
 Ln (38/12.5)= 12 K
 K= 0.09265 hr-1
 t1/2 = .693/ 0.09265 =
7.47 hrs.
At steady state (while receiving 300 mg q12 h), 180 mg of the
drug is excreted unchanged in urine during one dosing
interval. What is the renal clearance of this drug?

x9 |ƒ89`46 GH
 Fraction (f) = = =
x „…| I<JH (KL)

GH 0cV
 Fraction (f) = = = 0.6
I<JH (KL) ‚VV

 TBC = K Vd= 0.09265 x 11.76= 1.089 L/hr

 Renal clearance = f TBC= 0.6 x 1.089= .653 L/hr

After 15 days of antibiotic therapy, the kidney function of this
patient deteriorated and his creatinine clearance was found to
be 40 mL/min. What is the new half-life of the drug after this
change in the patient’s kidney function?

†‡†ˆ‰Š‹ˆŒ‡•
 KF= = 40/120= 0.3333
†‡†ˆ Ž•‡•Šˆ
 f= 0.6
/ 0/2 `g8^46
 T1/2failure =
[3 (xe 0) y0]
a.d
 T1/2failure = = 12.5hr
[V.j(.‚‚‚ 0) y0]
 K= 0.693/12.5= 0.05544 hr-1
What will be the steady-state maximum and minimum
plasma concentrations if this patient continues taking 300 mg
q12 h IV despite the change in his kidney function?

–—
 Cp∞ max = {™š )
˜ (

‚VV
 Cpmax ss = = 52.5 mg/l
00.aj(0 9{ .VddUUX 02 )

|}∞ ^5` = |}∞ ^4X . H B•

 Cpmin ss = 52.5e-.05544x12
 Cpmin ss = 26.9 mg /L
 Dose Adjustment in Hepatic Dysfunction
 Dose adjustment in patients with hepatic dysfunction is not an easy
task. This is because there is no single clinical test that can be used
for the assessment of liver function. Also, different metabolic
enzyme systems are affected to different degrees by the reduction in
liver function.
 The Child-Pugh classification has been used in clinical practice
for categorizing patients according to the severity of their liver
function impairment.
 This classification utilizes five different laboratory tests and clinical
conditions to assess the severity of liver disease: serum albumin,
total bilirubin, prothrombin time, ascites, and encephalopathy.
 Each of these parameters is classified and is given a score of 1, 2,
or 3 depending on the value of the parameter
 The total Child-Pugh score is calculated from the sum of the scores
for all the five parameters.

29
 Child-Pugh’s Classification for Patients
with Liver Diseases
Parameters Score
1 2 3
Serum albumin (g/dL) >3.5 2.8–3.5 < 2.8
Total bilirubin (mg/dL) < 2.0 2.0–3.0 > 3.0
Prothrombin time <4 4–6 >6
(seconds over control)
Ascites Absent Mild Moderate
Encephalopathy None Moderate Severe

 Patients having a score of 6–7 points classified as

group A (mild) (No adjustment)
 Patients having a score of 8–9 group B (moderate)
(25 % reduction of initial dose) (>60% metabolized)
 Patients having a score of 10–15 group C (severe)
(50 % reduction of initial dose).
30
Example:
 A 55-year-old female was admitted to the hospital after
developing an episode of ventricular arrhythmia. The
patient had history of multiple medical problems
including liver cirrhosis, hypertension, and ischemic
heart disease. Her laboratory values upon admission
were serum creatinine 1.1 mg/dL, serum albumin 3.2
g/dL, total bilirubin 4.5 mg/dL, and prothrombin time 8 s
more than control. Physical examination showed that the
patient is alert without any signs of encephalopathy, and
the patient has mild ascites. The physician wanted to
start the patient on lidocaine and asked you to
recommend an average starting dose of lidocaine.

31
Answer
Lidocaine is an antiarrhythmic drug that is completely metabolized. So
the patient’s liver condition may affect the clearance of lidocaine. It is
wise to calculate the Child-Pugh score for his patient to determine if dose
reduction is necessary.
Serum albumin 3.2 g/dL Score = 2
Bilirubin 4.5 mg/dL Score = 3
Prothrombin time 8 s > control Score = 3
Ascites Mild Score = 2
Encephalopathy Absent Score = 1
Total Child-Pugh score = 11
According to the Child-Pugh score, the starting dose of lidocaine in
this patient should be 50% of the average recommended dose of
lidocaine. Lidocaine dose can be adjusted after the start of therapy
according to the therapeutic and the adverse effects of lidocaine.

32
Alteration in Drug Pharmacokinetics in Obese
Patients
 Medications that have high lipid solubility tend to partition
into adipose tissue, and the volume of distribution in
obese patients for these drugs can be dramatically larger
than in normal weight patients.

 Examples of lipophilic drugs with larger volume of

distribution values in obese individuals are diazepam,
carbamazepine, and trazodone.

 However, hydrophilic drugs tend to not distribute into

adipose tissue so that the volume of distribution for many
water-soluble drugs is not significantly different in obese
and normal weight patients with some exceptions.

33
 Ideal body weight (IBW)
 Ideal body weight (IBW) were preferred in moderate to
highly lipophilic drugs when used.in obese patients.
 IBW (male) = 50 + 2.3 X height in inches > 60 inches

 IBW (Female) = 45 + 2.3 X height in inches > 60 inches

 Obese: if > 130% IBW.

 Inch = 2.54 cm; Foot = 12 inch.

34
 Example of Hydrophilic drugs
 The aminoglycoside antibiotics (gentamicin) are
hydrophilic drugs that are mainly distributed in the
extracellular fluid (ECF) and usually have an average Vd
of about 0.26.L/kg.
 It is recommended that in obese patients (patients
whose TBW is >130% of the IBW) the Vd for
aminoglycosides should be calculated based on
following Equation.
 In this equation, the difference between TBW and IBW
that represents the adipose tissues is multiplied by a
factor of 0.4 to account for the lower extracellular fluids
in adipose tissues:
Vd (L) = 0.26 (L/kg)[IBW + 0.4 (TBW – IBW)]
35
 Example of Lipophilic drugs
 Also, lipophilic drugs such as phenytoin usually have
high affinity to fat and are distributed to adipose tissues
more than their distribution to lean tissues.

 The Vd for phenytoin is usually calculated in obese

patients using following Equation. In this equation, the
difference between TBW and IBW, which represents the
adipose tissues, is multiplied by a factor of 1.33 to
account for the higher affinity of this lipophilic drug to the
adipose tissues:
Vd (L) = 0.7(L/kg)[IBW + 1.33(TBW – IBW)]

36