CHAPTER 13

MULTIPLE DOSING

A single dose of a drug is usually administered in order to attain therapeutic concentration of drug
in the 'plasma for a very brief period of time. For instance, a single dose of an analgesic (e.g., aspirin,
ibuprofen, or acetaminophen) is usually sufficient to treat an acute condition such as an occasional head­
ache. It is also not uncommon for a therapeutic agent to be administered in more than just one dose, but
for a relatively short period of time, e.g., if the condition being treated persists for 2 or 3 days. However,
in most clinical situations it is necessary that the drug be administered for relatively longer periods of time
(Le., on a chronic basis) in order to maintain therapeutic plasma concentrations for prolonged periods.
Examples of these situations include treatments that last a few weeks (e.g., antibiotics and sulfonamides),
or a few months, (e.g., hormones), or for periods extending into years (e.g., anti-diabetics and anti­
coagulants). While in most cases the therapeutic concentration of the medicinal agent in the plasma must
be maintained, in the case of some drugs, however, fluctuations between high and low levels of drug
concentration with respect to minimum effective concentration may in fact be preferred (e.g., penicillins).
During multiple dosing, when therapeutic levels of the drug must be maintained above a certain
concentration, the recommended dose of the drug is generally administered at the drug's biological half­
life intervals. For example, if the biological half-life of a drug is about 6 hours, then each dose of the drug
is administered every 6 hours. Since each succeeding dose is administered when about one-half of the
preceding dose is still in the body, the amount of drug remaining in the body from each successive dose
accumulates. Assuming that the dosing interval.is kept constant and the size of dose is not changed during
the course of therapy, the extent of accumulation of drug in the body then depends on the dosing interval.
It is also assumed that the drug follows linear pharmacokinetics and other pharmacokinetic parameters,
such as the volume of distribution, rate constant of elimination, and the clearance of drug, do not change
during the course of therapy. Obviously, a larger amount of drug will accumulate with each administered
dose if the dosing interval is less than the biological half-life of the drug. On the other hand, a smaller
amount of drug will accumulate with each administered dose when the dosing interval is greater than the
biological half-life of the drug. The following discussion examines the effect of dosing interval on the
accumulation and subsequent plasma concentration of drug in the body during multiple dosing.
INTRAVENOUS ADMINISTRATION
The simplest case is a drug which, when administered intravenously as a sihgle bolus dose,
follows linear pharmacokinetic and confers upon the body the characteristics of one-compartment open
model. As mentioned earlier, it is assumed that during multiple dosing, administration of earlier doses of
the drug do not affect the pharmacokinetics (Le., elimination, metabolism, clearance, etc.) of subsequent
doses of the drug. When administered intravenously, the entire drug dose appears in plasma immediately
after the dose is administered and drug elimination begins according to first-order kinetics. If the dosing
interval between each dose is such that the previous dose is virtually eliminated before the next· dose is
administered (e.g., if biological half-life of the drug is 3 hours and the drug is administered every 24 hours
(at least 8 times of biological half-life), the concentration of drug in plasma just before administration of
the next dose will be virtually zero (Le., there will be no accumulation of drug from each dose
administered). In such cases, administration of the second dose will yield a plasma profIle virtually
identical to the plasma profIle obtained after the administration of the first dose, because, during multiple
dosing the amount of drug remaining in the body from the previous administered dose is virtually zero.
Therefore, the concentration of drug in plasma versus time plot will exhibit a series of single-dose prOfiles
as shown in Fig. 13-1. . .
'I i

316 • Chapter 13

11 11 11
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DOSE NUMBER

Fig. 13-1: Plasma Profile When Dosing Interval Is Much Longer than Biological Half-Life.

If the dosing interval is relatively shorter than the time for virtual elimination of each dose (e.g., if
the biological half-life of the drug is 3 hours and the drug is administered every 9 hours), the fraction of
dose not eliminated from each previous dose accumulates as subsequent doses are administered. Thus, if a
second bolus dose is administered before the first dose is virtually eliminated, the concentration of drug in
plasma immediately after administration of the second dose is equal to the plasma concentration of drug
due to second dose plus the plasma concentration of drug due to the drug still remaining to be eliminated
from the first dose. Obviously, this plasma concentration will be greater than that obtained immediately
after the first dose.
Similarly, when the third bolus dose is administered, the fraction of dose still remaining to be
eliminated froIll the first two doses adds to the plasma concentration of drug due to administration of the
third dose. Consequently, the concentration of drug in plasma immediately after administration of the third
dose will be greater than the plasma drug concentration achieved immediately after administration of the
second dose (which, it will be recalled, was greater than the plasma concentration immediately after the
first dose was administered). Thus, a fraction of each administered dose accumulates in the body as
subsequent doses are administered
Since most drugs are usually administered at dosing intervals which are approximately equal to
their biological half-life, it follows that during a given dosing interval, approximately one-half of the
administered dose is eliminated and approximately one-half of the administered drug dose persists in the
body before the next dose is administered. Thus, when the second dose is administered, the amount of
drug in the body is increased due to the presence of approximately one-half of the first dose persisting in
the body. Similarly, just before administration of the third dose, approximately 25 % of the drug is still
remaining to be eliminated from the first dose, and about 50% of the drug is still remaining to be
eliminated from the second dose. Thus, with the administration of subsequent doses, the fraction of each
drug dose that persists in the body from the administration of previous doses accumulates. If the dosing
interval between each dose is less than the biological half-life of the drug, a substantial accumulation of
each drug dose occurs at the time of administration of the next dose.
Fig. 13-2 shows the accumulation of drug in plasma when dosing interval is equal to the biological
half-life of the drug.
 Multiple Dosing. 317

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2 3 4 5
DOSE NUMBER

Fig. 13-2: Accumulation of Drug during Multiple Dosing.

DRUG ACCUMULATION
To appreciate the extent of drug accumulation in the body following each dose, consider the case
of a drug which is administered as a 400 mg dose (D 400 mg) at its biological half-life intervals (dosing
interval is equal to biological half-life of the drug, i.e., 7: = t1l2). If the biological half-life of this drug is 6
hours, then the dosing interval 7: is also 6 hours. Since t1l2 = 6 hours, therefore the rate constant of
elimination, K is:
K == 0.693
t//l

== 0.693 0.1155 hr
6 hr
The mathematics of drug accumulation as each constant dose (400 mg) is adnf'mistered at the fixed
dosing interval of 6 hours is as follows. When the first dose is administered, the amount of drug in the
body is equal to the dose, i.e., 400 mg. After 6 hours; just before the second dose is given, 50% of the
first dose is eliminated and the amount of drug in the body is reduced to (0.5)(400 mg) = 200 mg, Le.,
amount of drug in the body ranged between 400 mg (maximum amount) and 200 mg (minimum amount)
during the first dose period. When the second dose is administered, the amount of drug in the body is
increased to 200 mg + 400 mg = 600 mg and 6 hours after administration of the second dose, 50% of the
amount of drug in the body is eliminated, Le., amount of drug in the body is reduced to (0.5)(600) mg =
300 mg. This means that amount of drug in the body ranges between 600 mg (maximum amount during
the second dose period) and 300 mg (minimum amount during the second dose period). For the first three
doses the following happens:
During the flI'st dose,
amount administered = 400 mg
amount eliminated = 200 mg
amount persisting in the body 400 mg - 200 mg = 200 mg
318 • Chapter 13

During the second dose,

amount from the first dose = 200 mg
amount administered =: 400 mg
amount in the body = 600 mg
(200 mg from the first dose and 400 mg from second dose)
amount eliminated = 300 mg
(100 mg from first the dose and 200 mg from second dose)
amount now persisting in the body 600 mg - 300 mg = 300 mg
(100 mg from the first dose and 200 mg from the second dose)
During the third dose,
amount from the first two doses = 300 mg
(100 mg from the first dose and 200 mg from the second dose)
amount administered = 400 mg
amount in the body = 700 mg
(100 mg from first dose, 200 mg from second dose, 400 mg from third dose)
amount eliminated 350 mg
(50 mg from first dose, 100 mg from second dose, 200 mg from third dose)
amount now persisting in the body 700 mg - 350 mg = 350 mg
(50 mg from first dose, 100 mg from second dose, 200 mg from third dose)
Thus, during the first dose, the amount of drug in the body ranged between a maximum of 400 mg
to a minimum of 200 mg and during the second dose, the range was between a maximum of 600 mg to a
minimum of 300 mg, and the maximum and minirilum amounts of drug in the body during the third dose
ranged between a high of 700 mg to a low of 350 mg. Comparing the maximum and minimum amounts of
drug in the body during the first three doses, the maximum amounts were 400 mg, 600 mg, and 700 mg
for the first, second, and third dose, respectively, i.e., showing an increase of 200 mg between the first
and second dose, but an increase of only 100 mg between the second and third dose. Similarly, the
minimum amounts of drug in the body during the first three doses were 200 mg, 300 mg, and 350 mg,
respectively, indicating an increase of 100 mg between the first two doses but an increase of only 50 mg
between the second and third dose. The increase in the amount of drug in the body becomes successively
smaller with each dose administered. This pattern indicates that with each successive dose, the maximum
amount of drug in the body increased 50% of the previous increase. For a comprehensive look at the
amount of drug in the body during multiple dosing of similar doses administered at fixed dosing intervals,
let us consider the elimination and persistence of the drug in terms of the percentage of each administered
dose. Table 13-1 lists the percentage of drug in the body following the administration of each dose.
In Table 13-1, the first column is dose number i.e., the first dose, the second dose, the third dose,
etc. The second column shows the breakdown of the amount of drug persisting iJ:l th~ body for each dose.
Column 3 indicates the cumulative total amount of drug in the body. The first line fof each dose is amount
of drug in the body immediately after the dose is administered, and this represents the maximum amount
of drug at the time of administration of that dose. The second line for each dose is the amount of drug in
the body just before administration of the next dose, and therefore this line represents the minimum
amount of drug up to the time of administration of the next dose. The last column (column 4) is the range
of amount of drug in the body (maximum and minimum amount of drug in the body) for each dose.
For the sake of simplicity, the decimal. fractions are avoided in this tabulation. The fractional
percentages in Table 13-1 have been rounded to the nearest whole numbers. For example, the percentage
of first dose remaining in the body just before the administration of the fourth dose is actually 12.5, but
this number is rounded off to 13. Similarly, the percentage of the first dose remaining in the body just
before the administration of the fifth dose is rounded off to 6 (instead of the actual number which is
calculated to be 6.125). For each of the doses listed in Table 13-1, the actual numbers representing the
percent age of first dose remaining in the body just before the next dose is administered should be 50, 25,
12.5, 6.25, 3.125, 1.562, 0.781, 0.391, 0.195, etc., but these are rounded off to 50,25, 13, 6, 3, 2, 1, 0,
0, and 0, respectively.
 Multiple Dosing. 319

Table 13-1
PERCENT DRUG IN THE BODY FOLLOWING EACH DOSE
Dose Percent Drug In The Body*
# Percent drug persisting for each dose Total Range
100 max
50 50 min
+ 100 150 max
25 + 50 75 min
III 25 + 50 + 100 175 max
13 + 25 + 50 88 min
IV 13 + 25 + 50 + 100 188 max
6+ 13+ 25+ 50 94 min
V 6+ 13 + 25 + 50 + 100 194 max
3 + 6+ 13 + 25 + 50 97 min
VI 197 max
g 6+ 99 min
a
,e VII 2+ 3+ 6+ 13 + 25 + 50 + tOO 199 max
,f 1 + 2+ 3 + 6+ 13+ 25+ 50 100 min
,It VIII 1 + 2+ 3+ 6+ 13 + 25 + 50+ 100 200 max
;t
0+ 1 + 2+ 3+ 6 + 13 + 25 + 50 100 min
.e
r IX 0+ 1 + 2+ 3+ 6+ 13 + 25 + 50 + 100 200 max
"
g min
0+ 0+ 1 + 2+ 3+ 6+ 13 + 25 + 50 100
y
X 0+ 0+ 1 + 2+ 3+ 6+ 13 + 25 + 50 + 100 200 max
n
0+ 0+ 0+ 1 + 2+ 3+ 6+ 13+ 25+ 50 100 min
e

"
* See text for explanation
d
It should be remembered, however, that the percentage of first dose remaining in the body never
attains a value of zero (Le., the drug, theoretically, is never completely elinlinated from the body). This is
because elimination is a first-order process meaning that the amount of drug eliminat¢ is always a fraction
it
of the amount of drug remaining to be eliminated from the body. However, wheh the amount of drug
It
remaining in the body becomes very small, so small that it may be difficult to detect the presence of drug
11
in the body or in the plasma, then, for all practically purposes, the drug is considered to have been
1
completely eliminated.
Table 13-1 shows that approximately 95% of the first dose is e1inlinated after about 4 or 5 doses
and the first dose is virtually eliminated after about 8 doses. After 8 doses, the amount of drug appears to
I reach a plateau, the maximum and minimum amounts (or concentrations) ranging between 200% and
100% of the dose. Comparing the breakdown for the 9th dose with the breakdown for the 8th dose, the
t
numbers in both rows of the second column are identical except that a zero is added for the first dose in
each row. Sinrilarly, comparing the breakdown for the 10th dose with that of the 9th dose, the numbers
are again the same except that another zero is added (for the second dose).
If continued to compare the breakdown for the 11th, 12th, 13th, and the nth dose, the numbers in
both rows of the second column will be identical except that a zero will be added for the first dose in each
row. Thus, the breakdown for each successive dose will be identical to that of the preceding dose except
'f I:

320 • Chapter 13

that the numbers in the rows representing the succeeding dose will be shifted one step to the right, i.e., the
maximum and minimum amounts (column 4) for all successive doses would remain the same as long as'
the drug is administered at the same dose level and at the same dosing interval.
From the data shown in Table 13-1, the following observations can be made:
(a) When the drug is administered at its biological half-life intervals (T = t1l2), one-half of each
administered dose is eliminated (lost) between the administration of each dose and one-half of the
administered dose persists in the body.
(b) When subsequent doses are administered, the fraction of each dose remaining in the body from the
.. previous doses undergoes persistence and elimination in the same manner as did the previous doses
when these doses were administered (Fig. 13-2), i.e., one-half of the dose remaining in the body from
, each dose .is eliminated and one-half persists in the body.
(c) Thus, a portion' of each administered dose is lost (elimination) from the body, and a portion of each
administered dose persists in the body. During administration of subsequent doses, the portion of each
dose not eliminated (i.e., persisting in the body) accumulates.
Therefore, during multiple dosing, concentration of drug in the body depends on (i) the fraction of
each dose persisting in the body, known as the persistence factor, (ii) the fraction of each dose eliminated
(lost) from the body, known as the loss factor, and (iii) the fraction of each dose accumulating in the body,
known as the accumulation factor.
PERSISTENCE FACTOR
As defined above, persistence factor represents the fraction of each dose that persists in the body
during multiple dosing. This is the fraction that was not eliminated. Therefore, the fraction of dose
persisting in the body can be determined from the equation describing the first-order rate process because
elimination is a first-order process. The first-order equation describing concentration of drug in the body
after administration of a dose is:
(13-1)
In equation (13-1), C is the concentration of drug at time t, Co is the concentration of drug at time 0, K is
the first-order rate constant of elimination and t is the time.
During multiple dosing, the first-order rate constant K is first-order rate constant of elimination,
and time t is dosing interval (T). Substituting dor t into equation (13-1), we have:

C=Cle- Kr ) (13-2)
· . amount of drug . 3 2) b .
SIDce concentratIOn = , equation (1 - may e WrItten as:.,
volume of d i s t r i b u t i o n "
D = Do (e- Kr ) (13-3)
Vd Vd
where, D is the amount of drug in the body, Do (= dose) is the amount of drug in the body at time 0, and
Vd is the apparent volume of distribution.
Dividing both sides of equation (13-3) by Do yields the following equation.
~ = e- Kr (13-4)
Do
In equation (13-4), the ratio DIDo represents the fraction of dose in the body at the end of the dosing
interval, Le., this ratio is the fraction of dose persisting in the body during the dosing interval, T. Equation
(13-4) is therefore equivalent to:
Persistence Factor = P =e-Kr (13-5)
 Multiple Dosing. 321

Ie According to equation (13-5), persistence factor (P) depends only on two factors: (i) K, the rate constant
is
of elimination and (ii) r:, the dosing interval.
EXAMPLE 13-1
The half-life of a drug is 6 hours. Calculate persistence factor if the dose is administered (a) every
:h 6 hours and (b) every 12 hours.
le
SOLUTION
Ie Since 1112 = 6 hours, therefore K = 0.693/t1l2 0.693/6 hr 0.1155/hr
:s (a) When r: = 6 hours, P = e-Kr
n
P = e-IO.Jl55Ihr)(6hr) = e-O· 693 = 0.5
h That is 50% of each dose will persist in the body before the next dose is administered at 6 hours intervals.
h
(b) When r: == 12 hours, P = e-Kr

If
P e-IO.1l55Ihr)(J2 hr) = e-1.386 = 0.25
d This means that when the dosing interval is 12 hours, 25% of each dose will persist in the body before the
next dose is administered.
LOSS FACTOR
Loss of drug from the body refers to drug elimination. The fraction of each dose not persisting in
the body represents the fraction of each dose that is lost (Le., eliminated from the body). Since the amount
of drug lost from the body (eliminated) plus the amount of drug still in'the body (persistence) is equal to
the amount of dose administered, the fraction of dose lost plus the fraction of dose persisting should be
equal to one. In other words,
Loss Factor == E == J Persistence Factor
Loss Factor == E == J-P== J_[K, (13-6)
EXAMPLE 13-2
If the biological half-life of a drug is 6 hours, calculate the Loss Factor if identical doses are
administered (a) every 6 hours, (b) every 12 hours.

SOLUTION
Since t1l2 = 6 hours, therefore, K 0.693/1112 = 0.693/6 hr = 0.1l55/hr
(a) When r: = 6 hours, the loss factor according to equation (13-6) is: :.:
E = 1 - e-Kr 1 - e-10. J155)16) 0.5
Thus, 50% of each dose will be eliminated before the next dose is administered.
(b) Similarly, in Example 13-1 it was found that when the drug is administered every 12 hours,
persistence factor = 0.25. Using equation (13-6) to calculate the loss factor,
E = 1 - P = 1 - 0.25 = 0.75
Thus, 75 % of each dose will be eliminated before the next dose is administered.
ACCUMULATION FACTOR
Accumulation of drug during multiple dosing is due to accumulation of each successive dose of
drug that persists in the body. The accumulation factor, S, after administration of n doses is determined
using the following ratio:
J_e- nKr
Accumulation Factor == S == K (13-7)
J e- r
322 • Chapter 13

After a large number of doses are administered, i.e., when n becomes sufficiently large.
value of the exponential term nKr increases, the term e-nKr approaches O. The accumulation factor
1 1
s ---
l_e- Kr
=----­
Loss Factor
EXAMPLE 13-3
If the biological half-life of a drug is 6 hours and identical doses are administered every 6 hOurs
calculate the accumulation factor after (a) 3 doses and (b) after 20 doses. .,

SOLUTION
Since t1l2 6 hours, thereforeK = O.693/6hr = O.1J55/hr,
(a) Accumulation factor after 3 doses: From equation (13-7),

1 e- nKr l_e-(3)(o.Jl55Ihr)(6hr) 1-0.125 0.875

S
l_e- Kr
= ·1_e-(o.1!55Ihr)(6hr) 1-0.5 0.5
1.75
The accumulation of drug after 3 doses is (1.75)(Dose) or 175% of the dose.
(b) Accumulation factor after 20 doses: Equation (13-8) may be used to calculate accumulation
factor after 20 doses,
1 -nKr 1 e-(20)(O.I155Ihr)(6hr) 1 0 1
s= -e
l_e- Kr
= l_e-(o.1l55Ihr)(6hr)
=
10.5
=-=2
0.5
After administration of 20 doses, each dose administered at 6-hour intervals, the accumulation of
the drug will be (2)(Dose) or 200% of the dose.
MATHEMATICAL TREATMENT
If the drug follows first-order elimination, then the concentration of drug in plasma during
multiple dosing can be predicted from the concentration of drug in plasma after the first dose, as long as
the size of each subsequent dose and the dosing intervals are held constant. Fig. 13-3 shows a typical
plasma profile after administration of the first dose. In this profile, the y-intercept is Co and the first-order
rate constant of elimination (K) is obtained from the slope of the straight line.
The first-order equation for concentration of drug in plasma at any time t is equation (13-1):

C =Co( e- K1 )

In this equation the exponential term represents fraction of dose persisting in the body, i.e., e-Kr, and Co is
concentration just after administration of the dose. Equation (13-1) may be written as equation (13-2):
Kr
C=Co(e- )

FIRST DOSE: Since plasma concentration immediately after administration of the first dose (Co) is the
maximum plasma drug concentration for the first dose:
(13-9)

Just before the second dose is administrated (at time = T), the plasma drug concentration is the
minimum concentration of drug in plasma for the first dose. Since equation (13-1) predicts drug
concentration at any time t after the first dose, it follows that at time t = T,

(13-tO)
 Multiple Dosing. 323

10

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z
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TIME (hr)

Fig. 13-3: Typical Plasma Profile After Administration of First Dose.

SECOND DOSE: When the second dose is administered, the maximum concentration of drug in plasma
(Cmax 1) is the sum of minimum plasma drug concentration after the first dose (Cmin 1) and concentration of
drug provided by the second dose. Since the same dose is given again, the second dose provides the same
concentration of drug as was obtained when the first dose was administered (i.e., Co):
(13-11)

Substituting the value of Cmin1 from equation (13-10) into equation (13-11):
Cmax2 = Co + Core- Kr )
(13-12)
Cmax2 ;Co(1+e- Kr )
Just before administration of the third dose, concentration of drug in plasma is the minimum
plasma concentration after the second dose (Cmin 2). This concentration can be determined using the same
rationale that was used for obtaining minimum concentration of drug in plasma after.:the first dose. The
minimum concentration after the second dose is obtained by multiplying plasma drug concentration at the
time of administration of the second dose (Crnax 2) with the persistence factor (e-Kj:
Cmi,,2 = (Cmax1 ) ([KT ) (13-13)

Substituting the value of Cmar 2 from equation (13-12) into equation (13-13):
Cmf,,2 =Co(1+e- KT )(e-KT ) (13-14)
THIRD DOSE: When the third dose is given, the maximum concentration in plasma is minimum
concentration after the second dose (Cmin 2) plus the concentration provided by the third dose. Since the
same dose is administered, the third dose provides the same concentration that was obtained when the first
dose was administered (i.e., Co). Therefore, maximum concentration of drug after the third dose is
Cmax3 = Co +Cmin2 (13-15)
Substituting the value of Cmin2 from equation (13-14) into equation (13-15):
324 • Chapter 13

Cmax3 = Co + Co(l + e- Kr ) ( e- Kr )
Cmax3 = Co(l + e- Kt + e-2Kt )
The minimum concentration of drug in plasma after the third dose is obtained in a manner similar
one used for determining the minimum pl(lsma drug concentration after the second dose:

(13-17)

Substituting the value of Cmax3 from equation (13-16) into equation (13-17):
C.
mm3
= C0 (1+e- Kr +e-2Kt )( e-Kr) (13-18)

FOURTH DOSE: Similarly, the maximum concentration of drug in plasma after the fourth dose is
Cmax 4 = C0 (1 + e -Kt + e -2Kt + e- 3Kt ) (13-19)

and the minimum concentration after administration of the fourth dose of the drug is
C.
mm4
== C0 (1 + e -Kt + e- 2Kr + e-3Kt )(e- Kt ) (13-20)

GENERAL EQUATIONS
A close examination of equations describing maximum and minimum concentrations of drug in
plasma after the administration of each of first four doses reveals that these equations follow a specific
pattern. To illustrate this pattern, equations (13-9), (13-12), (13-16), and (13-19) which describe the
maximum concentration after each of the first four doses are shown in a simplified form in Table 13-2.
These equations exhibit a geometric progression. According to geometric progression, each term,
after the first term, is obtained by multiplying the preceding term with a constant, called the common
ratio . .The first term in this series is Co and the common ratio is e-Kt• Therefore, the second term in this
series is Co multiplied by e-Kr = Co e-KT• Similarly, the third term is obtained by multiplying the second
term, Co e-KT, with the same common ratio, e-KT, and the third term is (Co e-K,)(e-K,) = Co e-2Kt•
Table 13-2
SIMPLIFIED FORMS OF EQUATIONS DESCRIBING Cmax

Dose # Equation Simplified Form Of Equation

1 (13-9) Co
2 (13-12) Co + Co e-Kt
Co + Co e­ 2Kt
n + Co e­
3 (13-16) .. ' ,

4 Kr
Co + Co e- + Co e­2Kt 3Kr
+ Co e­
Similarly, equations (13-10), (13-14), (13-18), and (13-20) which describe minimum concentration
of drug in plasma after each of the first four doses are shown in the simplified form in Table 13-3.
Table 13-3
SIMPLIFIED FORMS OF EQUATIONS DESCRIBING Cmin

Dose # Equation Simplified Form Of Equation

1 (13-10) Coe-Kr
2 (13-14) Co e-Kt 2KT
+ Co e­
3 (13-18) Co e-Kr 2Kt + Co e­
+ Co e­ 3Kt

4 2Kr + Co e­
Co e-Kr + Co e­ 3Kt + Co e-4Kt
 Multiple Dosing. 325

Comparing this series (Table 13-3) with the series describing the maximum the concentrations of
drug in plasma after each of the first four doses (Table 13-2), one fmds a similarity and a difference. The
similarity is that the common ratio, e'K\ is the same in both cases. The difference is that the first term is
different in the two series. The first term in the series in Table 13-3 is not Co as seen in Table 13-2, but it
is Co e'Kr. Thus, the second term in this series is (Co e'Kj(e'Kj, which is equal to Co e'2Kr. The thini term,
by defmition, is the second term (which is Co e'2Kj multiplied by the constant (which is e'Kj, i.e., the third
term is (Co e'2Kj(e'Kj = (Co)(e'3Kj.
MAXIMUM PLASMA CONCENTRATION, Cmax The maximum concentration of drug in plasma, after
the first, second, third, and the fourth dose is described by equations (13-9), (13-12), (13-16), and (13-19),
respectively. These equations are shown in a simplified form in Table B-2, As can be seen, these
equations exhibit the development of a generalized form. According to the development of this generalized
form (Table 13-2), the maximum concentration of drug in plasma after the administration of n doses can·
be expressed by the equation:

Cmaxn = C0 + C0 e- Kr + C0 e-1Kr + C0 e-3Kt + C0 e- 4Kt + .......... + C0 e-(n-I)Kt (13-21)

In this equation, CfIUJX n is maximum concentration of drug in plasma after administration of the nth
dose. Equation (13-21) is a general expression equation that can be simplified by mathematical procedures
to express maximum concentration of drug in the plasma after n number of doses as follows:
First, multiply both sides of equation (13-21) with (e'Kj to obtain equation (13-22). One writes
these two equations as follows:

(13-21)

(13-22)

Equation (13-22) is obtained from equation (13-21) by multiplying each member of the equation
(13-21) by e'Kt. Writing like terms of the right hand side members of both equations one under the other,
and subtracting equation (13-22) from equation (13-21) one obtains
Kt nKr
C _(e- )C =Cll-e- )
maxn maxn

or,

C (l-e- nKt )
C = --,,-0_----,,,--_ (13-23)
maxn l_e- Kt

Equation (13-23) describes maximum concentration of drug in plasma after the~dministration of n

doses.
MINIMUM PLASMA CONCENTRATION, Cmin As was seen earlier in the case of equations
describing the maximum concentration of drug in the plasma after the first four doses, one also sees the
development of a similar pattern when one examines equations (13-10), (13-14), (13-18), and (13-20),
each of which describes the minimum concentration of drug in plasma after the first, second, third, and the
fourth dose, respectively.
These equations, shown in a simplified form in Table 13-3, also exhibit the development of a
similar generaliZed pattern. According to the development of this generalized form (Table 13-3), the
minimum concentration of drug after administration of n doses can be expressed by the equation:

Cmin n =COe -Kr + COe-lKt + COe-3Kr + COe-4Kt +.......... + COe -(n)Kt (13-24)
326 • Chapter 13

where,
Cmin n is the concentration of drug in plasma at the end of dosing interval of the nth dose, and
Gun n-I is the concentration of drug in plasma just before the beginning of dosing interval of the nth ',"''''''''''''
Equation (13-24) can also be simplified by mathematical procedures similar to those \lSed;®
simplify equation (13-21), The simplified equation that expresses the minimum concentration of ~m
plasma after n number of doses is derived by writing the two equations as follows:
Cmin n -- Coe -Kr + Coe-2Kr + Coe -3Kr + Coe -4Kr + ...... + Coe-(n)Kr (13-24)
( e-KT)C, = C0 e-2Kr + C0 e-3Kr + C0e-4Kr + .•... .+ C0 e-(n)Kr + C0 e-(n+I)Kr
, .
mlnn (13-25)
Equation (13-25) is obtained from equation (13-24) by mUltiplying each member of the equation
(13-24) by e·Kt and writing the like terms of the right hand side members of the equations one under the
other, Subtraction of equation (13-25) from equation (13-24) gives .
C.
mlnn
-( e -Kt)C.
mlnn
=Ce- Kr
0
Ce-(n+l)Kr
0 (13-26)

Equation (13-26) can be simplified to

C.
nlmn
(1 e- KT )= C0 (e- Kr _e-{n+l)Kr)

or, . (1- e -Kr)=coe-Kt(l_ e -nKT)

Cmlnn

and

This equation can be written as follows:

(13-27)

Substituting Cmaxn for its value from equation (13-23) into equation (13-27):
Cminn = Cmaxn ( e- Kr ) (13-28)
The relationship shown in equation (13-28) can also be established when equations shown in Table
13-2 are compared with those shown in Table 13-3. The equations shown in Table 13-3 are identical to
those shown in Table 13-2, except that each member of right-hand side of equation in Table 13-3 is
multiplied by the term e'Kr, Le., minimum concentration of drug in plasma after each dose is equal to the
product of maximum concentration of drug in plasma after that dose and e·n , as shown in Table 13-4.
Table 13-4 :.:
MINIMUM CONCENTRATION AFTER EACH INTRAVENOUS DOSE

Dose Minimum Plasma Drug Concentration

First (Cmax I)(e-K,
Second (Cmax2)(e,K,
Third (Cmax3)(e-K,
Fourth (Cmax4)(e· K,
Fifth (Cmat .5)(e,K,

According to this pattern, the minimum concentration of drug in plasma after n doses will be
equation (13-28):
 Multiple Dosing. 327

From equations (13-23) and (13-27), it is seen that one can calculate maximum and minimum drug
plasma concentrations after administration of any number of equal doses given at fixed time intervals,
provided the following parameters are known: Co (initial concentration), K (rate constant of elimination), r
to (dosing interval), and n (number of doses administered).
in
EXAMPLE 13-4
Calculate maximum plasma drug concentration after the administration of fourth dose, if 50 mg
~) bolus doses are given intravenously every 4 hours. Given Co = 3 mg/L and K = 0.2/hr.
5) SOLUTION
Using equation (13-23), the maximum plasma drug concentration after the fourth dose is
In
C =Co(l e- nKr )=(3mgIL)(1_e-(4)(o.2Ihr)(4hr))
Ie
max 4 1_e- Kr 1 e-(O.21hr)(4hr)

5) = (3 mg I L)(1 0.04076) = 3 mg X 0.95924 = 5.226 miL

1- 0.4493 0.55067 g
EXAMPLE 13-5
Calculate the maximum and minimum plasma concentrations of a drug after administration of the
fourth dose, if 50 mg bolus dose is given intravenously every 4 hours. The volume of distribution of the
drug is 40 L, and the rate constant of elimination is 0.07/hr.
SOLUTION
Since dose = 50 mg and apparent volume of distribution = 40 L, therefore
C = Dose 50mg IL=1.25mgIL
o
Volume of distribution 40 L
(a) Using equation (13-23), the maximum concentration of drug after the fourth dose is
C (l_e- nKr ) (1.25 mg I L)(1_e-(4)(O.07lhr)(4hr) )
C = 0 =____~~1_e-(O.07Ihr)(4hr)
__~~~~~____~
max 4 1_e-Kr
= (1.25 mg I L)(0.6737) = 3.45 miL
e 0.2442 g
D (b) Using equation (13-28), the minimum concentration of drug after the fourth dose is:
S
Cmin4 = (Cmax4)(e-Kr )=(3.45 mg I L)(e-(O.07!hr)(4hr))
e
(3.45 mg I L )(0.7558) = 2.61 mg I L
';,:
STEADY-STATE CONCENTRATIONS
The steady-state concentration of drug in plasma (or the plateau level) is reached when the values
of the maximum concentration of drug in plasma (Cmax-) and the minimum concentration of drug in plasma
(Cmin) become constant for each successive dose. This can happen only when the equations describing the
maximum concentration of drug in plasma and the minimum concentration of drug in plasma are not'
affected by n (the number of dose). In other words, the equations describing the maximum and minimum
concentrations of drug in the plasma at steady-state do not include a term containing n. This would be case
when the value of the exponential term e,nK1: in these equations approaches a value of zero. At that time the
equations describing the maximum and minimum plasma concentrations will exhibit a plateau...In order for
the value of e,nKr to approach a value of 0, n must have a sufficiently large value~ Wben this happens, the
amount of drug eliminated from the body becomes equal to the amount of drug administered. into the body,
and equilibrium is reached between drug input and drug output. .
MAXIMUM CONCENTRATION, CI1UlX $S

According to equation (13-23), the maximum concentration of drug in the plasma at steady-state is .
II

328 • Chapter 13

the maximum concentration drug plasma concentration after the administration of a large number of
(Le., Cmaxssis CinLit n), when n (number of doses administered) becomes very large. At very large vCl\tlesl(~f
n, the exponential term (e-llKj in the numerator of equation (13-23) approaches a value of zero ~"Ule
numerator now becomes equal to Co (1 - 0) = Co. Therefore, equation (13-23) is reduced to
C = Co
maxss i_e- Kr
MINIMUM CONCENTRATION, Cminss
The minimum concentration of drug in the plasma at steady-state (Cmin ss) can be derived from
equations (13-27) and (13-28). When n becomes very large (after administration of a large number of
doses), the exponential term (e·nKj in the numerator of equation (13-27) approaches a value of O.
Therefore, at large values of n, the numerator in equation (13-7) is equal to Co (1 - 0) = Co e-Kr•
Therefore, equation (13-27) becomes
Cmin ss = i Co-Kr (e- Kr ) = Cmax ss (e- Kr ) (13-30)
-e
EXAMPLE 13-6
From the data provided in Example 13-5, calculate Cmaxss and Cminss.

SOLUTION
From the data provided in Example 13-5:
Co = 1.25 mg/L, Kr = 0.28, and e-Kr = 0.756
(a) Using equation (13-29), the maximum concentration of drug in plasma at steady-state is
C
maxss
= i_e-
Co
Kr

= (1.25 mg / L) = (1.25 mg / L)(0.6737) = 5 12 m / L

i_e-(O.07Ihr)(4hr) 0.244 . g

(b) Using equation (13-30), the minimum concentration of drug in plasma at steady-state is

Cminss = (Cmaxss )(e- Kr )

=(5.12 mg / L)(e-(O.07Ihr)(4 hr) )
= (5.12 mg / L)(0.756) = 3.87 mg / L

EXAMPLE 13-7
The following data were obtained after administration of a 300 mg intravenous bolus dose of an
antibiotic. Calculate Cmaxss and Cminss if a 300 mg dose is given every 6 hours.
Time (hr): 1 2 3 4 6 8 10 12
Concentration (mcg/mL): 36 33 29 26 20 16 13 10

SOLUTION
A plot of the data is shown in Fig. 13-4.
This graph shows that upon administration, the drug confers upon the body the characteristics of
one-compartment pharmacokinetic model.
From Fig. 13-4: Co = 41 mcg/mL and t1l2 = 6 hours_
0.693
Therefore, K =- - = 0.1155 / hr, and e-
Kr
= e-<J·693 = 0.5
6 hr
 Multiple Dosing. 329

100

80

::::J
--
E
OJ
U
50

g 40
z
0
i=
«
0::
I­
Z
W
(,)
z 20
0
(,)

10~----.-----.-----,-----.-----,--- ___
o 2 4 6 8 10 12
TIME (hr)

Fig. 13-4: Plot of Data in Example 13-7.

Substituting these values into equation (13-29):

Co
i _e- Kr
41meglmL 41mglL 82 I L
i_e-(O.1J55Ihr)(6hr) = 1-0.5 = meg m

Similarly, substituting the values of Cmaxss, K, and dnto equation (13-30):

Cminss = (Cmaxss )(e- Kr )

= (82 mg I L)( e-(O.l155Ihr)(6hr) ) = (82 mg I L)(O.5) = 41 mg I L <-.

EXAMPLE 13-8
A 300 mg bolus dose of an antibiotic administered intravenously gave the following data.
Calculate the maximum and minimum concentration of drug in the plasma at steady-state if a 300 mg dose
is given intravenously every 6 hours.
Time (hr): 2 4 6 8 10 12.
Concentration (mcg/mL): 25.2 19.9 17.8 15.8 12.5 11.2

SOLUTION
A plot of the data is shown in Fig. 13-5.
This plot shows that upon administration the drug confers the characteristics of one-compartment.
pharmacokinetic model on the body. ' ..
330 • Chapter 13

From this graph, Co = 30 mcg/mL and 1112 8 hours.

K = 0.693 0.693 = 0.0866 hr
1m 8 hr
Kr = (O.0866/hr)(6hr) = 0.5196,

therefore, e-
Kr e-IJ.5196:= 0.595.

100

80

50

40
z
0
i=
~
I­
Z
W
()
z
0
()
20
•

10~----.-----.----,,----.-----.----~

o 2 468 10 12
TIME (hr)

Fig. 13-5: Plot of Data in Example 13-8.

Substituting these values into equation (13-29):

Co 30meglmL = 30 meg ImL =74.1 me ImL

Cmaxss =1 e- Kr = 1_e-(o.0866lhr)(6hr) 1-0.595 g
Similarly, substituting the values into equation (13-30):
C.
mm,Ss
={Cmaxss )e- Kr =(741
•
meglmL)e-(O.0866Ihr)(6hr)
= (74.1 meg I mL){0.595) 44.1 meg I mL
EFFECT OF DOSING INTERVAL
Comparing the values of the maximum and minimum concentrations of drug in the plasma at
steady-state fOWld in examples 13-7 and 13-8, one finds that the value of Cmmss was equal to the value of
Co in Example 13-7, but the value of Cnuilss was greater than the value of Co in Example 13-8. Also, it is
seen that in Example 13-7, Cmaxss was equal to twice the value of Co, but Cmaxss was greater than two times
the value of Co in Example 13-8. This is because in Example 13-7, the dosing interval was equal to the
biological half-life of the drug, and in Example 13-8 the dosing interval was less than the biological half­
life of the drug which was responsible for the difference in the accumulation of the drug in the body. Table
13-5 shows the effect of dosing interval on drug accumulation.
 Multiple Dosing. 331

TABLE 13-5
EFFECT OF DOSING INTERV AL ON Cmax ss AND Cmin ss
Dosing Persistence Loss Accumulation Cnuu: ss Cmin 5S

Interval Factor Factor

,= 0.251112 0.84 0.16 6.29 6.29Co 5.29Co
,= 0.501112 0.71 0.29 3.41 3.41Co 2.41Co
,= 0.75 t1l2 0.59 0.41 2.47 2.47Co 1.47Co
,= 1.00 t1l2 0.50 0.50 2.00 2.00Co 1.0OCo
, 1.25 t1l2 0.42 0.58 1.73 1.73Co 0.73Co
,= 1.5011lz 0.35 0.65 1.55 1. 55Co 0.55Co
,= 1.751112 0.30 0.70 1.42 1. 42Co 0.42Co
,= 2.00 IlIZ 0.25 0.75 1.33 1.33Co 0.33Co
, 2.50 t1l2 0.18 0.82 1.21 1.21Co 0.21Co
,= 3.00 t1l2 0.13 0.87 1.14 1. 14Co 0.14Co
,= 0.06 0.94 1.07 1.07Co 0.07Co

The following explanation clarifies the difference in the values of maximum and minimum steady­
state concentrations of drug in plasma found in examples 13-7 and 13-8:
(a) Dosing interval equal to biological half-life
When dosing interval is equal to biological half-life of the drug, i.e., when, = t1l2,
Persistence Factor = P = e- Kr = e-O· 695 =0.5,
Loss Factor = 1- Persistence Factor = 1-0.5 = 0.5, and

Accumulation Factor = 1 = 1 = _1_ = 2

1- Persistance Factor 1 0.5 0.5
(b) Dosing interval less than biological half-life
But, when dosing interval is less than biological half-life of the drug, the term K t' becomes small,
and the exponential term e·Kr will have a larger value. Therefore, persistence factor (e'K~ is increased and
consequently the loss factor (1 - persistence factor) is decreased. Decrease in loss factor will increase
accumulation factor, which indicates increased accumulation of drug in the body and accounts for larger
values of Cmox S5 and Cmin ss.
(c) Dosing interval greater than biological half-life
If, on the other hand, the dosing interval is greater than biological half-life ()f the drug, the term
K, will become large and hence e-Kr will have a smaller value. Therefore, persistence factor will decrease,
the loss factor will increase, and consequently the accumulation factor will decrease, indicating less
accumulation of drug in the body, and the Cmin ss and Cmax ss values will also decrease.
EXAMPLE 13-9
From the data given in Example 13-8, calculate the maximum and minimum concentrations at
steady-state (Cmaxss and Cminss) if ,was made 12 hours.
SOLUI'ION
When, = 12 hours, K, = (0.0866)(12) 1.0392, and e-KT e- J·039Z = 0.3537. Therefore,
C
max.s
= l_e-
Co
KT

= 30 mcg / mL = 30 mcg / mL = 30 mcg / mL =46.44 mc / mL

l_e-(o.o866Ihr)(J2hr) 1-0.3537 0.6463 g
332 • Chapter 13

== (46.44 meg / mL)( e-(O.0866Ihr)(12hr) )

(46.44 meg / mL)(0.3537) == 16.44 meg / mL
RELATIONSHIP BETWEEN Cmarss and Cminss
During mUltiple dosing, when equal doses are given at fixed dosing intervals, the difference
between maximum and minimum concentrations of drug at steady-state (Cmnx ss - Cmln ss) is always equal to
Co~. This can be seen if we subtract equation (13-30), equation for the minimum concentration of drug at
steady-state from equation (13-29), equation for maximum steady-state concentration of drug. Subtraction
yields:
C C
c0 C KT C (1 e- KT )
= C0
moxss - minss = 1 e- KT
0
1 e- Kr
(e- ) 0
1 (e- KT ) (13-31)

In linear pharmacokinetics, since Co is a function of dose and apparent volume of distribution, the
only factors that will influence Co are the dose and the apparent volume of distribution. Thus, if the dose
and apparent volume of distribution do not change during multiple dosing, the difference between
maximum and minimum concentrations of drug in plasma at steady-state will be always equal to Co.
FACTORS INFLUENCING STEADY-STATE CONCENTRATION
Equations (13-29) and (13-30) describe steady-state concentrations of drug. These equations show
that Cmnx ss and Cmin ss depend on Co, K, and T. In linear pharmacokinetics, Co is proportional to D (because
Co = DIVd), and if the volume of distribution (Vd) and rate constant of elimination (K) do not change
during the course of therapy, the maximum and minimum concentrations at steady-state will depend only
on (i) dose and (ii) dosing interval.
EFFECT OF DOSE According to equation (13-29),

Cmaxss = l_c;-KT ' and since Co == ~ , therefore,

d

(13-32)

If a dose D" (instead of the dose D) is administered, and assuming no change in dosing interval,
apparent volume of distribution, and rate constant of elimination of the drug, then the maximum
concentration at steady-state (Cmnx ss") is given by
D"
C " == (13-33)
maxss V (1-e- Kr )
d

Dividing equation (13-32) by equation (13-33),

D

(13-34)

Vd(J _e- Kr )
Using the same rationale for minimum concentrations at steady-state, it can be shown that
Cminss D
(13-35)
Cminss" D"
Thus, changes in the size of the drug dose administered will correspondingly increase or decrease
the steady-state maximum and minimum concentration of drug in the plasma. The following example
illustrates the effect of dose on steady-state concentrations.
 Multiple Dosing. 333

EXAMPLE 13-10
Administration of a single 50 mg intravenous bolus dose of a drug gave the following data: one­
compartment model with Co = 2 mcglmL and K 0.1125/hr. Calculate the maxinmm and minimum
concentrations at steady-state in the same patient having different dosing regimens: (a) one regimen is
administered a 50 mg dose every 8 hours and (b) another regimen is a 35 mg dose (instead of 50 mg dose)
every 8 hours from the start of the treatment.
:e
:0 SOLUTION
at (a) Kr = (0.1J25/hr)(8hr) = 0.9, e·Kr = e.()·9 0.4066
'n 2 meg I mL 2 I mL I
1_e-(o.1l25Ihr)(8hr) ---""--=3.37
1 0.4066
meg mL

I)
Cminss = 1­ )
Ie
:e = 2meglmL (1_e-(O/125Ihr)(8hr))
n
1 e-(O,1/25Ihr){8hr)

= 2 meg I mL (0.4066) = 1.37 me I mL

1 0.4066 g

"e (b) Since only the dose is changed, K and r are unchanged in the same patient. Therefore, the
values of e,Kr and (1 - e-K ,) remain unchanged. The value of Co, however, will change because
e
dose is changed. Assuming linear pharmacokinetics, since Co = DIVd, therefore
y
(old Co)(new dose) (2 meg I mL)( 35 mg)
new Co 1.4 meg I mL
old dose 50 mg

new Co
new Cmaxss =1 e-Kr

) 1.4 meg I mL ImL

= 1- e-(O.IJ25Ihr )(8hr) ---'=--- =2.36 meg I mL
1 0.4066
new Co -Kr
1 new Cminss = 1-e-Kr (e )

1.4 meg I mL (1- e-(0ll25lhr )(8hr) )

1_e-(O.1I25Ihr)(8hr) "
":.,

= 1.4 meg ImL (0.4066) =0.96 me I mL

1-0.4066 g
From Example 13-10, comparing the maximum and minimum concentrations of drug in plasma at
steady-state, it is seen that
old Cmaxss 3.37 meg I mL = 1.43
new Cmaxss 2.36 meg I mL
old Cminss = 1.37 meg I mL =1.43
new Cminss 0.96 meg I mL
old dose 50 mg
and 1.43
new dose 35 mg
Which is in agreement with equations (13-34) and (13-35).
,­,­

334 • Chapter 13

EFFECT OF DOSING INTERVAL The effect of dosing interval on the steady-state minimum and
maximum concentrations of drug in the plasma is not as simple and straight-forward as the effect of dose.
This is because in linear pharmacokinetics, the size of dose is directly proportional to the value of Co and
any change in the size of dose has a linear effect on the concentration of drug in the plasma at steady-state.
Dosing interval is not related in a similar linear manner to the terms used to calculate minimum and
maximum concentrations of drug in plasma at steady-state. In equations used for calculating steady-state
concentrations of drug, dosing interval appears in the exponential terms. Therefore, the relationship
between dosing interval and steady-state concentrations becomes more complicated, and it is not possible
to relate the effect of dosing interval on steady-state concentrations with a simple relationship.
EXTRAVASCULAR ADMINISTRATION
Extravascular administration, particularly administration by the oral route is the more popular
route used during multiple dosing. Although accumulation of drug during extravascular administration is
very similar to that found during intravenous administration, the magnitude of accumulation of drug is not
similar in both cases. In extravascular administration, immediately after the administration of the drug
dose, the concentration of drug in plasma first increases (due to absorption), reaches its peak, and then
decreases (due to very little absorption). In intravenous administration, the concentration of drug in plasma
is at its peak at the time of administration, but peak concentration in extravascular administration is usually
less than that seen in intravenous administration, because the entire drug-dose is not placed in the blood
stream all-at~once. The drug appears in plasma because of absorption, and the magnitude of increase in
concentration of drug in plasma depends upon the rates of absorption, distribution, and elimination of the
drug. Thus, the steady-state concentrations of drug during multiple dosing following extravascular
administration depend on the rates of absorption, distribution, and elimination of the drug.
The simplest case is a drug which, when administered extravascularly as a single bolus dose,
confers upon the body the characteristics of one-compartment model. It is assumed that during multiple
dosing, earlier doses of the drug do not affect pharmacokinetics of subsequent doses, that is, the processes
of absorption, elimination, metabolism, and clearance, etc., of the drug remain unchanged, and the
apparent volume of distribution of the drug also remains unchanged. It is also assumed that the entire
administered drug dose is completely absorbed (F = 1), and following absorption, elimination begins
according to first-order kinetics. If the dosing interval between doses is· such that the previous dose is
virtually eliminated before the next dose is administered (e.g., if biological half-life of the drug is 3 hours
and the drug is administered once a day), the plasma concentration versus time plot will exhibit a series of
single-dose profiles. But, if the dosing interval is approximately equal to half-life of the drug, the drug
accumulates in the body as each successive dose is administered.
Accumulation of the drug during multiple dosing in extravascular administration is similar to
accumulation of drug during intravenous administration. The main difference ~tween the two is
absorption of the drug. If the drug is absorbed rapidly and completely, the plasma profiles are very similar
except that the graph depicting extravascular administration exhibits the absorption phase. For most
conventional formulations, except those intended to provide delayed or modified release of the active
ingredient (sustained or prolonged release and enteric-coated dosage forms), the extravascular dosage form
is formulated to provide rapid absorption. Therefore, the terminal portion of plasma profile (which
exhibits predominantly elimination) following extravascular administration is very similar to the terminal
portion of the graph obtained following intravenous administration of the drug.
Thus, determination of plateau levels during multiple dosing of extravascularly administrated
dosage forms is similar to the determination of plateau levels attained during multiple dosing by
intravenous administration, except that during extravascular administration, the rate constant of absorption
(Ko) must be taken into consideration. During extravascular administration, the y-intercept B (obtained by
back-extrapolating the terminal linear portion of elimination phase) is used in place of Co (the y-intercept
used during intravenous administration). It should be mentioned, however, that the numerical value of the
y-intercept B obtained during extravascular administration is usually less than the numerical value of the y­
intercept Co obtained following intravenous administration.

-
 Multiple Dosing. 335

STEADY-STATE CONCENTRATIONS
Since the minimum concentration of drug in plasma during a dosing period is the concentration
just prior to administration of the next dose, and if dosing interval is such that the next dose is
administered in the post-absorptive phase of the previous dose, one can assume that most of the drug from
each dose was absorbed before the next dose was administered. Therefore, the rate of drug absorption
would not affect the minimum concentration attained during each dose as well as at the steady-state.
However, since the maximum concentration attained after each dose occurs at the time of maximum
concentration (tmax) , and tmax is a complex function of absorption and elimination rate constants, the
utilization of maximum concentration values after each dose to determine the maximum plasma
coRCentration at steady-state becomes relatively complicated. A simpler relationship is ,given here.
MAXIMUM CONCENTRATION, Cmaxss
The maximum drug plasma concentration at steady-state is calculated using the equation:

C = (B) (e- R ) (13-36)

maxss J _e- Kr
In this equation B is the y-intercept obtained by back-extrapolating the terminal linear portion of
plasma profile to time zero following the administration of the first dose, K and r have been defined
previously, and R is a factor which accounts for the absorption and elimination rate constants of the drug.
The factor R is calculated using the relationship:
(13-37)
In equation (13-37), tmax is the time of peak concentration after the first dose. For aU practical'
purposes, if Ka > > > K (i.e., Ka is at least 5 times greater than K), the plasma-profile shows a distinct
and sharp peak enabling one to read tmax from the graph as a good approximation. However, if the plasma
profile does not exhibit a sharp peak and/or if it is difficult to read tmax from the graph, it can be calculated
using the equation:
InKa InK Ina-Inp
-----=---- = (13-38)
Ka -K a-p
MINIMUM CONCENTRATION, Cminss
The minimum concentration of drug in plasma following extravascular administration of n doses is
described by the equation:
(1_e- nKr )(e- Kr ) (J-e- nG )(e-G )]
Cminn (B) [ 1 -Kr 1 -6 (13-39)
-e e
where, Clllin n = minimum concentration of drug in plasma during the nth dose, B = bpck-extrapolated y­
intercept of the terminal linear phase after the first dose, K = elimination rate constant, r = dosing
interval, G = KaT, and Ka = absorption rate constant.
By setting n 1 in equation (13-39) an expression for the minimum plasma concentration of drug
following the first dose (eminl) can be obtained. When n = 1, equation (13-39) becomes:
(1 e- Kr )(e- Kr ) (l-e- G)(e-G)]
Cmin 1 =(B) 1 -e-Kr I-G
[ -e (13-40)

When n becomes large (Le., when steady-state is attained), an expression for minimum plasma
concentration of drug at steady-state is obtained from equation (13-39). When n becomes large, the
exponential terms e-nKf and e""G approach 0, and equation (13-39) becomes

Cm ,"" =(B J[ 1:-::K' --l__

e-e-G_-=G] (13-41)
336 • Chapter 13

In the post-absorptive phase, G (the product of Ka and T) becomes large, and fh..~·a.+.....

exponential term e,G approaches O. Equation (13-41) is then reduced to

KT
Cminss = 1 B_KT (e- )
-e
EXAMPLE 13-11
From the following data obtained after oral administration of a single 500 mg dose of an anlib~Qtic;
calculate maximum and minimum steady-state concentrations of the drug if a 500 mg oral 4Qse is
administered every 4 hours. . ;, ...

Time Concentration Time Concentration Time Concentration':':

(br) (mcg/mL) (br) (mcg/mL) (br) (mcg/lIlL)
0.5 198 2.0 28.0 5.0 16.7
1.0 27.0 3.0 23.7 6.0 14.0
1.5 28.3 4.0 20.0 7.0 12.0
SOLUTION
A plot of concentration of drug in plasma as a function of time is shown in Fig. 13-6,
BaCk-extrapolation of the terminal linear portion gives B = 40 mcg/mL. The initial data points
representing the predominantly absorption phase are feathered to yield the absorption phase. The graph
shows that the drug confers the characteristics of one-compartment model on the body. From the graph,
K=_ln40 In20 = 0.6931 0.1733/hr
(0-4) hr -4 hr
KT = (0.1733/hr)(4hr) = 0.6932, therefore, e'KT e-O,693 = 0.5.
Ka = - ln40-lnl 3.6889 = 1.7567/ hr
(0-2.1)hr -2.1 hr
G = (Ka) (r) (1. 757/hr)(4 hr) 7.028, therefore, e,G = e,7.028 = O.
100

50
B=40
:::J
E
-­
0>
u
E
20
~

Z
0

~
10
I­
Z
ill
U 5
z
0
U

1
0 1 2 3 4 5 6 7
TIME (hr)

Fig. 13-6: Plot of Data in Example 13-11. "

 Multiple Dosing. 337

From the graph it appears that the time of maximum concentration of drug in the plasma (tmax) is
about 1.5 hours. According to equation (13-38), tn/ax is:
In -InK
t =--::!--­
max K K
a

In 1.7567 -lnO.1733 2.3162

=--------- 1.463 hr
1.7567/ hr 0.1733/ hr 1.5834/ hr
R = (K)(t max ) = (0.1733/ hr)(1.463hr} = 0.2535
Therefore, e-
R
= e.fJ·2535 = 0_ 776_
Substituting the values of B, G
e-R, e- , and e- KT into equations (13-36) and (13-41),
C
maxss = 1-eB-KT (-R)
e

= 40 meg / mL (0. 776) == _31_.0_4_-=--_ 62. 08 meg / mL, and

1 a5 a5

Cm;"" =(BJ[I~-::K' I~;G]

=(40 meg / mL)[ 0_5 _0_] ( 40 meg / mL)( 1- 0) = 40 meg / mL
1 0.5 1 0
If the approximate values of JG, and tmax were used in calculating CmllX ss and Cn/ill 55, the answers
obtained are not likely to be significantly different from the answers obtained using the more accurate
values, because the approximate values of the rate constant of absorption and the time of maximum
concentration are not significantly different from their accurate values.
For example, using Ka = 1.7325/hr and tmax = 1.5 hours,
R (Ke)(tmax) = (0.1733/hr)(i.5 hr) = 0.25995, therefore,
e-R = e.fJ·2599 = O. 771

G = (Ka)( 'Zj = (i. 7325/hr)(4 hr) 6.93, therefore,

e-G = e.(,·93 = O.OOi
Substituting the values into equations (13-36) and (13-41),
R
Cmaxss =1 B_KT (e- )
-e
40 meg / mL (0.771) = 30.84 meg / mL =61.68 meg / mL, and
1-0.5 0_5

C.." (B J[ e-::"
I I ~:-G ]
5 0.001 ]
( 40 meg / mL)[ 0. = (40 meg / mL)( 1 0.001) 39.96 meg / mL
1-0.5 1-0.001

It will be noticed that in this example, the dosing interval was equal to the biological half-life of
the drug, therefore the minimum plasma concentration of drug at steady-state was approximately equal to
the y-intercept B (Fig. 13-6). However, the maximum concentration of drug at steady-state was not equal .
to twice the value of B because administration of drug via extravascular route requires time for absorption.
338 • Chapter 13

RELATIONSHIP BETWEEN C11UU:SS and Cminss It was shown in equation (13-34) that during
multiple dosing the difference between the maximum and minimum concentrations of drug in
steady-state was always equal to Co (as long as there is no change in the dose, volume of
dosing interval). In extravascular administration the difference between maximum and
concentrations of drug in plasma at steady-state, obtained by subtracting equation (13-41) from equation
(l3~36) is not as simple as was seen during intravenous administration, but is a complex function oillie
factors that determine these concentrations.
FACTORS INFLUENCING STEADY-8TATE CONCENTRATION
From equations (13-36) and (13-41), it is seen that during extravascular administration, the
mirumum concentration of drug in the plasma at steady-state depends on three factors: (i)the y-interceptB,
(ii) the rate constant of elimination, and (iii) the dosing intervaL On the other hand, the maximum
concentration of drug in the plasma at steady-state depends on four factors: (i) the y-intercept B, (ii) the
rate constant of elimination, (iii) the dosing interval, and (iv) the rate constant of absorption. The factors
influencing Cltlin ss are similar to those seen during intravenous administration, because the parameter B in
the extravascular administration (the y-intercept of the resolved plasma profile after administration of the
first dose) is similar to the parameter Co in the intravenous administration (the y-intercept of the plasma
profile after administration of the first dose). However, the factors affecting the maximum concentration at
steady-state differ in the two cases, because, during extravascular administration, there is an added factor,
Ka. In linear pharmacokinetics, B is directly proportional to dose, because equation (12-5) of Chapter 12:
B= (F )(D)(KaJ
(12-5)
(Vd)(Ka -KJ
and it is assumed that the values of F, Vd, Ka, and K do not change during the course of therapy. The
steady-state maximum and minimum concentrations of drug in the plasma therefore depend only on (i)
dose and (ii) dosing intervaL
EFFECT OF DOSE According to equation (13-41),
e-Kr
C.
mmss
= ( B J l_e- Kr
[

(13-43)

The minimum concentration of drug in plasma at steady-state (Cmin ss-) followiri~ the administration
of a dose D" (assuming no change in dosing interval, volume of distribution, rate constant of absorption,
elimination rate constant, and the fraction of dose absorbed) is given by
Kr G
( F)(D")(K J][ e- e- ]
CminssH = [ (Vd)(Ka -;J l_e- Kr l-e- G (13-44)

Dividing equation (13-43) by equation (13-44),

(13-45)
Cminss" D"
Similarly, using the same rationale, it can be shown that
Cmaxss D
= (13-46)
 Multiple Dosing. 339

IS Thus, an increase or decrease in the dose will correspondingly increase or decrease the steady­
It state concentrations. The following example illustrates the effect of dose on steady-state maximum and
d minimum concentrations of drug in the plasma.
n
n EXAMPLE 13-12
e Administration of 500 mg oral dose of an antibiotic gave the following data: B = 70 mcg/mL, Ka
0.711hr, and K = 0.139/hr. Calculate steady-state maximum and minimum plasma concentration of
drug if (a) 500 mg dose is administered every 6 hours, or (b) 400 mg dose is administered every 6 hours.

e SOLUTION
I
"
(a) From the data provided:
11 -InK
e
s
InO.71-lnO.139
= 1.6308
11
e = 2~6~
0.71 I hr-0.139 I hr 0.571 I hr
a R (K )(tmax) =(0.139 I hr)( 2. 856hr) =0.397 , therefore,
.t
e-R = e-fJ.397 = 0.6723
K. (0. 139/hr)(6 hr) = 0.834, therefore,
) e-Kr e-fJ·834 = 0.4343
(1 e-K ? (1 - 0.4343) = 0.5657
G (0.7l1hr)(6 hr) = 4.26, therefore,
e-G = e-4·26 = 0.0141
Substituting these values into equation (13-36):
B
Cmaxss = 1 )

70 meg ImL (0.6723) = 47.061 ImL 83.19me ImL

1-0.4343 0.5657 g
Similarly, substituting these values into equation (1341),

C (B{l e-::
m;." K, l~-:G] ..
( 70me ImL)[ 0.4343 _ 0.0141 J=(70me ImL)[0.4343 0.0141J
g 1-0.4343 1-0.0141 g 0.5657 0.9859
(70 meg I mL)(O. 7677 -0.01430) = 52. 73 meg I mL
Using equation (13-43), the minimum concentration at steady-state is
C B (e- Kf )
millS' =1 e- Kr
70 I mL 0.4343 = 30.401 meg I mL =53. 74 me I mL
1 0.4343 0.5657 g
It is seen that the minimum concentration of drug in plasma at steady-state obtained using equation
(1341) is slightly larger than that obtained using equation (1343). This is because the factor e-G does not
approach O. Therefore, the second exponential term on the right-hand side of equation (1341) still has a
340 • Chapter 13

finite value. The value of minimum concentration of drug in the plasma at steady-state obtained using
equation (13-41) is more accurate than the value obtained using equation (13-43).
(b) When the dose is changed from 500 mg to 400 mg, the values of P and R are not changed
because the factors affecting P and R (D, K, and Ka) are not affected. Therefore, e-KT and e-R are also
unchanged. The value of y-intercept, B will change because of change in dose. ASSuming linear
pharmacokinetics,
new B = (old B )(newdose) = (70 meg I mL)(400 mg) 56 meg I mL
old dose 500 mg

C B* (e- R ) = 56 meg I mL (0.6723) = 37.65 I mL = 66.55 me I mL

maxss 1 e- Kr 1-0.4343 0.5657 g

):;:: 56 meg I mL (0.4343) = 24.32 I mL 42.99 meg I mL

1-0.4343 0.5657
From Example 13-12 it is seen that
old = 83.19 meg I mL = 1.25
new Cmaxss 66.55 meg I mL

old = 53.74 meg I mL = 1.25

new Cminss . 42.99 meg I mL

and, old dose = 500 mg = 1.25

new dose 400 mg
which is in agreement with equations (13-45) and (13-46).

EFFECT OF DOSING INTERVAL It was mentioned earlier (in the section dealing with intravenous
administration of bolus doses), that the effect of dosing interval on the plasma minimum and maximum
concentrations of drug at steady-state (Cmin ss and Cmax ss) is not simple and straight-forward. During
extravascular administration, the same reasoning holds true. In linear pharmacokinetics, the size of dose is
directly proportional to the value of y-intercept of the plasma concentration versus time plot, and any
change in the size of dose has a linear effect on the concentration of drug in the plasma at steady-state.
Dosing interval is not related in a similar linear manner to the terms used in calculating the minimum and
maximum concentrations of drug in plasma at steady-state. In equations used for cal~ulating steady-state
concentrations of drug, dosing interval appears in the exponential terms. Therefoh~, the relationship
between dosing interval and steady-state concentrations becomes more complicated, and it is not possible
to relate the effect of dosing interval on steady-state concentrations with a simple relationship.

SUGGESTED READING
1. M. Gibaldi and D. Perrier, "Pharmacokinetics," 2nd ed., Marcel Dekker, 1982.
2. "Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring," W. E. Evans, 1. J.
Schentag, and W. J. Jusko, eds., 3rd ed., Applied Therapeutics, 1995.
3. W.A.Ritschel, "Handbook of Basic Pharmacokinetics," 3rd ed, Drug Intelligence Publications, 1986.
4. "Remington: The Science and Practice of Pharmacy," 21st ed., Lippincott Williams & Wilkins, 2006.
5. D. Mungall, ed., "Applied Clinical Pharmacokinetics," Raven Press, 1983.
6. L. Benet, "Pharmacokinetics: A Modem View," Plenum Press, 1984.
 Multiple Dosing. 341

19
PRACTICE PROBLEMS
13-1. The biological half-life of a drug is 5 hours. Calculate the persistence factor if identical doses are
~d
administered every (a) 6 , or (b) 12 hours.
~o
13-2. The biological half-life of a drug is 4 hours. Calculate the loss factor if identical doses are
ar administered every (a) 6 , or (b) 12 hours.
13-3. The biological half-life of a drug is 4 hours and identical doses are administered every 6 hours.
Calculate the accumulation factor after the administration of: (a) 2 doses, (b) 3 doses, (c) 4 doses,
(d) 5 doses, and (e) 20 doses.
1~-4. Calculate the maximum and minimum plasma concentrations of a drug after the administration of
the fourth dose. The drug, upon administration, confers the characteristics of one-compartment
pharmacokinetic model on the body. Each dose is 80 mg administered intravenously as a bolus
injection every 4 hours, the apparent volume of distribution of the drug is 40 L, and the rate
constant of elimination is O. 07/hr.
13-5. Calculate the maximum and minimum plasma concentrations of a drug after- the administration of
the third dose. The drug confers the characteristics of one-compartment pharmacokinetic model on
the body. Each dose is 50 mg administered intravenously as a bolus injection every 4 hours, the
apparent volume of distribution of the drug is 40 L, and the rate constant of elimination is 0.07/hr.
13-6. Calculate the maximum and minimum plasma concentrations of a drug after administration of the
thirty-sixth dose of the drug. The drug confers the characteristics of one-compartment model on
the body. Each dose is 50 mg administered intravenously as a bOlus injection every 4 hours, the
apparent volume of distribution of the drug is 40 L, and the rate constant of elimination is 0.07/hr.
13-7. The following table details the concentration of drug in the plasma as a function of time after the
administration of a single 300 mg intravenous bolus dose of an antibiotic. Calculate the minimum
and maximum steady-state concentrations of drug in the plasma if a 300 mg rapid intravenous
bolus dose is given every (a) 12 , (b) 8 , or (c) 4 hours.
Time Concentration Time Concentration
(hr) (mg/L) (hr) (mg/L)
IS
0.5 0.925 4.0 0.500
n
1.0 0.845 5.0 0.420
.g
2.0 0.710 6.0 0.352
is
3.0 0.595 8.0 0.250
.y 13-8. The following table details the concentration of drug in the plasma as a function of time after the
administration of a single intravenous bolus dose of an antibiotic. Calculate the minimum and
d
maximum concentrations of drug in the plasma at the plateau level if the same dose is
.e
administered (a) once a day, (b) every 10 hours, or (c) every 3 hours'l~
p
e Time Concentration Time Concentration
(hr) (mcg/mL) (hr) (mcg/mL)
2.0 455 8.0 195
4.0 345 10.0 150
6.0 260 12.0 115
13-9. The following table details the concentration of drug in the plasma as a function of time after the
administration of a single 500 mg oral dose of an antibiotic. Calculate the maxinlum and minimum
concentrations of the drug at steady-state if a 500 mg dose of the antibiotic is administered every .
(a) 8 , (b) 16 , or (c) 24 hours.
Time Concentration Time Concentration Time Concentration
(hr) (mg/L) (hr) (mg/L) (hr) (mg/L)
1 2.88 8 2.00 20 0.73
2 3.25 12 1.45 24 0.53
4 2.85 16 1.02 28 0.38
342 • Chapter 13

13-10. Blood level data following a single 300 mg oral dose of a drug are shown below. '-'".....lJ,>I

maximum and minimum concentrations at steady-state if the patient is given a 300 mg

every 6 hours.
Time Concentration Time Concentration
(hr) (mcg/L) (hr) (mcg/L)
0.5 650 6.0 585
1.0 900 8.0 425
2.0 1100 10.0 310
4.0 800 12.0 255
13:11. Blood level data following a single intravenous dose of an antibiotic are shown below. Calculate
the minimum and maximum concentrations of drug in plasma at plateau level if the same dose is
administered (a) once a day, (b) every 10 hours, or (c) every 3 hours.
Time Concentration Time Concentration

2.0 8.0 234

4.0 414 10.0 180
6.0 312 12.0 138
13-12. Blood level data following intravenous administration of a 500 mg bolus dose of an antibiotic are
shown below. Calculate the minimum and maximum steady-state concentrations of the drug in the
plasma if a 300 mg intravenous bolus dose is given every (a) 12, (b) 8 , or (c) 4 hours.
Time Concentration Time Concentration
(hr) (mg/L) (hr) (mg/L)
0.5 1.4800 4.0 0.8000
1.0 1.3520 5.0 0.6720
2.0 1.1360 6.0 0.5632
3.0 0.9520 8.0 0,4000
13-13. Blood level data following intravenous administration of a single 450 mg dose of an antibiotic are
shown below. Calculate the minimum and maximum steady-state concentrations of drug in plasma
if a 300 mg rapid intravenous bolus dose is given every (a) 12 , (b) 8 , or (c) 4 hours.
Time Concentration Time
(hr) (mg/L) (hr) (mg/L)
0.5 1.295 4.0 0.700
1.0 1.183 5.0 0.5&~
2.0 0.994 6.0 0,493
3.0 0.833 8.0 0.350
13-14. Blood level data following intravenous administration of a single 550 mg bolus dose of an
antibiotic are shown below. Calculate the minimum and maximum steady-state concentrations of
drug in plasma if a 300 mg rapid intravenous bolus dose is given every (a) 12 , (b) 8 , or (c) 4
hours.
Time Concentration Time Concentration
(hr) (mg/L) (hr) (mg/L)
0.5 1.6650 4.0 0.9000
1.0 1.5210 5.0 0.7560
2;0 1.2780 6.0 0.6336
3.0 1.0710 8.0 0,4500