One Compartment Open Model

IV bolus

1
 Introduction

 Compartment models are often used to describe transport of material in

biological systems.
 A compartment model contains a number of compartments, each
containing well mixed material.
 A compartment model could also represent an ecological system where
the material could be energy, the compartments could represent
different species of animals and plants, and the flow between
compartments could account for uptake and loss of food (or energy). In
this case we would base the equations on laws describing conservation
of energy.
 Compartment models also arise in physiology, where the material could
be oxygen that is transported with the blood between deferent organs
(compartments) in the body.
 PHARMACOKINETIC MODEL

One of the primary objective of pharmacokinetic

models is to develop a quantitative method to
describe the relationship of drug concentration or
amount in the body as a function of time. The
complexity of the pharmacokinetics model will
vary with the route of administration, the extent
and duration of distribution into various body
fluids and tissues. The process of elimination and
the intended application of the pharmacokinetics
model .
 There are wide Varity of potential uses of
pharmacokinetic models which include

 Prediction of drug concentration in body and plasma or

tissues.
 Calculation of dosage regimen.
 Quantitative assessment of the effect of disease on drug
disposition.
 Elucidation of the mechanism of disease induced
alteration of the drug disposition.
 Determination of the mechanism for drug to drug
interaction.
 Prediction of drug concentration versus effect relationship.
There are 3 primary types of pharmacokinetic
models

Compartmental

Non-compartmental

Physiological
 Compartmental model

Compartmental model describes the

pharmacokinetics of drug disposition by grouping
body tissues that are kinetically indistinguishable
and describes the transfer of drug between body
tissues in term of rate constant.
 Noncompartmental models

Noncompartmental models describe the

pharmacokinetics of drug disposition using
time and concentration averaged parameter.
 Physiological models

Physiological models attempt to describe

drug disposition in terms of realistic

physiological parameters such as blood flow
and tissue partition coefficient's
 Sketch of a compartment model.
Material can be stored in the boxes and transported between boxes .

SOURCE O O

O O O

O O DRAIN
One, Two and Three Compartment Models
 ONE COMPARTMENT OPEN MODEL

The body is considered as a single, kinetically

homogeneous unit.
This model applies only to those drugs that are

distributed rapidly throughout the body.

Drugs move dynamically in an out of this

compartment
One compartment
12
More than one compartment
13
 One compartment open model
14

 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).

 One compartment open model
15

 The simplest kinetic model that describes drug disposition

in the body, which considers 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.

In a one-compartment model, we make two
important assumptions:

1) Linear pharmacokinetics –

By this, we mean that elimination is first order

and that pharmacokinetic parameters (ke, Vd,
Cl) are not affected by the amount of the dose.
Of course, a change in dose will be reflected by a
proportional change in plasma concentration.
 In a one-compartment model, we make two
important assumptions:

2) Immediate distribution and equilibrium

of the drug throughout the body.

Considering these assumptions, we can easily describe the

Cp vs t profile of a drug after an iv bolus injection (the same
principles apply to other routes of administration as well)
One compartment:
18
Properties of a Pharmacokinetic Compartment
19

1. Kinetic homogeneity. A compartment contains tissues that

can be grouped according to similar kinetic properties to
the drug allowing for rapid distribution between tissues
2. Although tissues within a compartment are kinetically
homogeneous, drug concentrations within a compartment
may have different concentrations of drug depending on
the partitioning and binding properties of the drug.
3. Within each compartment, distribution is immediate and
rapidly reversible.
4. Compartments are interconnected by first-order rate
constants. Input rate constants may be zero order
 One compartment:
20

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:

elimination rate  k  X
 One compartment open model

D  k t
C e
Vd
Drug Conc (C)

C= concentration
D= dose
Vd: Volume of distribution
k: elimination rate constant
t: time
Time

21
 How to distinguish one comp?

Plotting log(C) vs. time yields a

straight line
log (C)

Time

22
Fundamental parameters in one compartment
23

Apparent Volume of Distribution (Vd)

Elimination rate constant (K)
Elimination half life (t1/2)
Clearance (Cl)
Apparent Volume of Distribution (Vd)
24

Vd= 10 L Vd= 100 L

The real Volume of Distribution has physiological meaning and is
related to body water
25

Total body water 42

L
Plasma Plasma volume 4 L

Interstitial Interstitial fluid volume 10 L

fluid

Intracellular Intracellular fluid volume 28 L

fluid
 Apparent Volume of Distribution
26

 Drugs which binds selectively to plasma proteins, e.g.

Warfarin have apparent volume of distribution smaller than

their real volume of distribution

 Drugs which binds selectively to extravascular tissues, e.g.

Chloroquines have apparent volume of distribution larger

than their real volume of distribution. The Vd of such drugs
is always greater than 42 L (Total body water)
 Apparent Volume of Distribution
27

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
 Apparent Volume of Distribution
28
 In general, drug equilibrates rapidly in the body. When plasma or any
other biologic compartment is sampled and analyzed for drug content,
the results are usually reported in units of concentration instead of
amount

 Each individual tissue in the body may contain a different concentration

of drug due to differences in drug affinity for that tissue. Therefore, the
amount of drug in a given location can be related to its concentration by
a proportionality constant that reflects the volume of fluid the drug is
dissolved in

 The volume of distribution represents a volume that must be considered

in estimating the amount of drug in the body from the concentration of
drug found in the sampling compartment
Apparent Volume of Distribution: Mathematics
29

 In order to determine the apparent volume of distribution

of a drug, it is necessary to have plasma/serum
concentration versus time data

dose X0
Vd  
initial conc. C 0
 Apparent volume of distribution estimation
30

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:
dose X0
Vd  
initial conc. C 0
 1- Plot log(C) vs. time
31
7

6.8
Log (Conc)

6.6

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
 2- Plot the best-fit line
32
7

6.8
Log (Conc)

6.6

6.4

6.2

5.8
0 1 2 3 4 5 6

Time
 3-Extrapolate to the Y-axis intercept (to
estimate C0)
33
7

6.8
Log (Conc)

6.6

6.4

C0
6.2

5.8
0 1 2 3 4 5 6

Time
 4-Estimate Vd
34
7

dose X0
6.8
Vd  
initial conc. C 0
Log (Conc)

6.6

6.4

Log(C0)
6.2

5.8
0 1 2 3 4 5 6

Time
 The Extent of Distribution and Vd in a 70 kg
Normal Man
35

% Body
Extent of Distribution
Vd, L Weight

5 7 Only in plasma
5-20 7-28 In extracellular fluids
20-40 28-56 In total body fluids.
In deep tissues; bound to
>40 >56
peripheral tissues
 Elimination rate constant (K)
36

Elimination rate constant represents the fraction of drug

removed per unit of time

k has a unit of reciprocal of time (e.g. minute-1, hour-1, and day-

1)

With first-order elimination, the rate of elimination is directly

proportional to the serum drug concentration

Elimination rate constant estimation
37

1. Plot log(C) vs. time

2. Plot the best-fit line

3. Calculate the slope using two points on the best-fit

line
4. Estimate k:

k   Slope  2.303
 1- Plot log(C) vs. time
38
6.8

6.7

6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
 2- Plot the best-fit line
39
6.8

6.7

6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
 3- Calculate the slope using two points on the
best-fit lin
40
6.8

log(C1 )  log(C2 )
6.7

Slope 
t1  t 2
6.6
Log (Conc)

6.5

6.4

6.3
(Log(C1), t1)
6.2

6.1
(Log(C2), t2)

6
0 1 2 3 4 5 6

Time
 4- Estimate k
41
6.8

6.7
k   Slope  2.303
6.6
Log (Conc)

6.5

6.4

6.3

6.2

6.1

6
0 1 2 3 4 5 6

Time
 Elimination half life (t1/2)
42

The elimination half life is sometimes called

‘‘biological half-life’’ of a drug

It is defined as time taken for the amount of drug

in the body as well as plasma concentration to

decline by ½ or 50% of its initial value.
Elimination half life (t1/2) estimation
43

Two methods:
 From the value of k:
0.693
t1/ 2 
k

 Directly from Conc vs. time plot

 Select a concentration on the best fit line (C1)
 Look for the time that is needed to get to 50% of C1  half-life
 Clearance (Cl)
44

Clearance is a measure of the removal of drug from

the body
Plasma drug concentrations are affected by the

rate at which drug is administered, the volume in

which it distributes, and its clearance
A drug’s clearance and the volume of distribution

determine its half life

 Clearance (Cl)
45
 Clearance (expressed as volume/time) describes the removal
of drug from a volume of plasma in a given unit of time (drug
loss from the body)
 Clearance does not indicate the amount of drug being
removed. It indicates the volume of plasma (or blood) from
which the drug is completely removed, or cleared, in a given
time period.
 Figures in the following two slides represent two ways of
thinking about drug clearance:
 In the first Figure, the amount of drug (the number of
dots) decreases but fills the same volume, resulting in a
lower concentration
 Another way of viewing the same decrease would be to
calculate the volume that would be drug-free if the
concentration were held constant as presented in the
second Figure
 Clearance (Cl)
46

the amount of drug (the number of

dots) decreases but fills the same
volume, resulting in a lower
concentration
Clearance (Cl)
47
 Clearance (Cl)
48

 The most general definition of clearance is that it is ‘‘a

proportionality constant describing the relationship between

a substance’s rate of elimination (amount per unit time) at a
given time and its corresponding concentration in an
appropriate fluid at that time.’’
 Clearance can also be defined as ‘‘the hypothetical volume of

blood (plasma or serum) or other biological fluids from which

the drug is totally and irreversibly removed per unit time.’’
 Clearance (Cl) estimation
49

For ALL LINEAR pharmacokinetics (including one

compartment) , clearance is calculated using:

dose
Cl 
AUC
where AUC is the area under the concentration
curve (it will be discussed later)
 Clearance (Cl) estimation
50

For One compartment pharmacokinetics , clearance

is calculated using:

Cl  k  Vd
 Clearance (Cl)
51

Drugs can be cleared from the body by different

pathways, or organs, including hepatic
biotransformation and renal and biliary excretion.
Total body clearance of a drug is the sum of all the
clearances by various mechanisms.

Cl t  Clr  Cl h  Clother
(Cl t , Clr and Clh  total, renal, and hepatic Cl)
 Elimination rate
52

The elimination rate at any time can be calculated

using:
 Elimination rate = k*X(t)
OR
 Elimination rate = Cl*C(t)

where
 X(t) is the amount of drug in the body at time t,
 C(t) is the concentration of drug at time t
 Area Under the Conc. Time Curve
(AUC) calculation
53

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
 AUC calculation: Model dependent
54

With one compartment model, first-order

elimination, and intravenous drug administration,
the AUC can be calculated using:

Dose C0
AUC  
k  Vd k
 AUC calculation: Model independent
55

1200

1000

800

600

400

200

0
0 2 4 6 8 10 12
 AUC calculation: Model independent
56

1200

1- Divide the area into different parts

1000
based on the observed concentration
points (parts 1-5)
800

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12
 AUC calculation: Model independent
57

1200

1000
2- Calculate the area for each part of the
parts 1,2,3 and 4 (until the last observed
800 concentration) using trapezoidal rule

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12
 Trapezoidal rule
(Trapezoid =‫) شب&ه& لا&&منحرف‬
58

C1

C 2  C1
area   (t 2  t1 )
C2 2

where C = concentration
t = time

t1 t2
AUC calculation: Model independent
59

3- For part 5 (area between the last

observed concentration and infinity)
use the following equation:

C* C*
area 
k
 AUC calculation: Model independent
60

1200

1000
4- The total AUC (from zero to infinity) is the
sum of the areas of parts: 1,2,3,4, and 5
800

AUC0  AUC1  AUC2  AUC3  AUC4  AUC5

600

400 1

200
2
3
4 5
0
0 2 4 6 8 10 12
 Fraction of the dose remaining
61

Fraction of dose remainig (F = X(t)/X0) is given by

the following equation:
 k t
Amount at time t X 0  e  k t
F  e
dose X0
since t1/2= 0.693/k, the equation can be represented
as:

t
t
 0.693
 1  t1 / 2
Fe t1 / 2
 
2
 Time to get to certain conc.
62

Time to get to certain concentration (C*) is given by:

 k t C0
C*  C 0  e  k t
e 
C*
 C0 
k  t  ln 
 C *
 C0 
ln 
t  C * 
k
Applications of one compartment model
63

Case 1: Predicting Plasma Concentrations

Case 2: Duration of Action

Case 3:Value of a Dose to Give a Desired Initial

Plasma Concentration
 Case 1: Predicting Plasma Concentrations
64

 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 )
2. Calculate the plasma concentration at 3 h
 Case 1: Predicting Plasma Concentrations
65

1. Calculate the initial concentration (C0 )

dose 20 mg
C0    1 mg/L
Vd 20 L

2. Calculate the plasma conc. at 3 h

 K t -(0.1)(3)
C  C0  e  1 e  0.74 mg/L
 Case 2: Duration of Action
66

The duration of action of a drug may be considered

to be the length of time the plasma concentration
spends above the MEC. Its determination is best
illustrated by example 2.
 Case 2: Duration of Action
67
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?
 Case 2: Duration of Action
68

As indicated in the diagram (previous slide) 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?

 C0 
ln  
 C *   1 
t  ln   / 0.1  12.0 hr
K  0.3 
 Case 3: Value of a Dose to Give a Desired Initial Plasma
Concentration
69

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
C0  dose  C 0  Vd
Vd
mg
dose  5  20 L  100 mg
L
Examples

70
 Example 1
71

Ten 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.
 Example 1
72

Time (hr) Conc. (ng/ml)

1 90.0
2 68.0
4 40.0
6 21.5
8 12.0
10 7.0
 Example 1
73

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)
 Example 1
74

2.5

2
y = -0.1243x + 2.0832
R2 = 0.9995
1.5
log (Conc)

0.5

0
0 2 4 6 8 10 12
time (hr)
 Example 1
75

The elimination rate constant can be obtained from

the slope:
K  Slope  2.303
 (0.1243)  (2.303)  0.286 hr 1

Another way to calculate the slope is using:

log(C1) - log(C2)
Slope 
t1 - t2
 Example 1
76

Another way to calculate the slope (if you do not

have the ability to do regression) is using:
log(C1) - log(C2)
Slope 
t1 - t2
where (C1,t1) and (C2,t2) are two different conc.
time points

It is important to note that the first method for

calculating the slope is more accurate
 Example 1
77

Calculating the slope using the second method:

log(40) - log(21.5)
Slope   -0.13481
4-6
Note that the value of the slope is similar to the
value estimated using the first method (-0.1243)
 Example 1
78

the biological half-life of the drug elimination (t½):

The volume of distribution (Vd):

0.693 0.693
t 0.5    2.42 hr
K 0.286
dose 10 10
Vd   2.0832 
C0 10 121.12
mg 10 6 ng L
 0.083   3  83 L
ng/ml mg 10 ml
 Example 1
79

Intercept = log (C0)

2.5
C0= 10intecept

2
y = -0.1243x + 2.0832
R2 = 0.9995
1.5
log (Conc)

1
y = -0.1243x + 2.0832
2
R = 0.9995

0.5

0
0 2 4 6 8 10 12
time (hr)
 Example 1
80

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 conc. To get to 50 ng/ml :

 C0   121.12 
ln   ln  
t  C *    50   3.1 hr
K 0.286
 Example 2
81
 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
 Expected plasma concentration at 10 AM.
 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.
 Example 2
82

Elimination rate constant:

K  0.693  0.693  0.116 hr 1
t 0.5 6
Initial concentration:
 The conc. at 12:00 noon (6 hrs after the
first dose) is 5 µg/ml:

C (t  5)  C0  e  k t
C (t  5) 5
 C0   k t
  0.116   6  10 ug/ml
e e
 Example 2
83

Apparent volume of distribution:

C(t=6hrs)= 5 ug/ml. Since the half life is 6 hrs, C0 =
10 ug/ml.
X0 250 mg
VD   -3
 25000 ml  25 L
C0 μg 10 mg
10 
ml μg
Expected plasma concentration at 10 AM

K  0.693 /t 0 .5  0.693 / 6  0.1155 hr -1

C(t  4)  C 0  e  Kt  6.3 μg/ml

 Example 2
84

Duration of action of the first dose

C   10 
ln  0  ln  
t   C *  3  10.42 hr
K 0.1155
Total body clearance

Cl  K  VD  2.89 L/hr
Fraction of the dose in the body 5 hours after the
injection 5
 1 6
F     0.56
2
 Example 2
85
 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
Total amount = amount from the first dose + amount from
the second dose = 125 + 250 = 375 mg
 Example 2
86

Duration of action of first dose only if dose

administered at 6:00 AM was 500 mg

t d  10.42 hr  6 hr  16.42 hrs

Note that 6 hrs (one t0.5) is needed for the amount in
the body to decline from 500 mg to 250 mg
 Example 3
87

The therapeutic range of a drug is 20-200 mg/L.

After an intravenous bolus injection of 1.0 gm
followed by regression analysis of the
concentration of the drug in plasma (in units of
mg/L) versus time (in hours), the following linear
equation was obtained
log Cp  2  0.1t
Calculate the following
 Duration of action
 Total body clearance
 Rate of elimination at 2 hours
 Example 3
88

From the equation:

log Cp  2  0.1t  log(C0 )  slope  t
The following were estimated:

C0  10 2  100 mg/L

K  Slope  2.303  (0.1)  (2.303)  0.23 hr 1

X 0 1000 mg
VD    10 L
C 0 100 mg/L
 Example 3
89
Duration of action:
C   100 
ln  0  ln  
td   C *    20   7 hr
K 0.23

Total body clearance= K∙Vd=(0.23)(10) =2.3 L/hr

Rate of elimination at 2 hours:
Elimination rate = Cl*C(t=2) = 2.3*63 =145 mg/hr

log(Cp(t  2))  2  (0.1)(2)  1.8

 Cp(t  2)  101.8  63 mg/L
90