MULTIPLE DOSE REGIMEN

INTRODUCTION
 Drugs are rarely used in single doses to produce an acute
effect
 But, drugs are administered in successive doses to produce a
chronic or prolonged effect
 The goal in the design of dosage regimens is to achieve and
maintain drug concentrations in plasma or at the site of action
that are both safe and effective
 That is to maintain the drug concentration with in the
therapeutic window (Below the minimum toxic concentration
and above the minimum effective concentration)
 Toxicity would result if doses are administered too frequently,
whereas, effectiveness would be lost if the dosage rate are too
infrequent
 The two parameters important in dosage regimen are
The size of the dose of the drug
The frequency of drug administration (time interval between
doses)
 INTRODUCTION…
Effect of frequency of administration of a drug on plasma drug
level
Plasma Drug Concentration

Minimum toxic concentration

Therapeutic
B Window
Minimum toxic concentration

C
Time
A – Too frequent dosing B – Proper dosing C – Inadequate
frequency
 DRUG ACCUMULATION
 When drugs are administered on multiple dose regimen, each
dose (after first dose) is administered before the preceding
doses are completely eliminated
 This results in a phenomenon known as ‘drug accumulation’,
where the amount of the drug in the body (represented by
plasma concentration) builds up as successive doses are
administered
 But, after seven doses of the drug at an interval equal to the
drug half-life, the maximum and minimum amounts in the body
becomes fairly constant
 This is called ‘Steady State Condition’
 At this stage, the amount of the drug lost during dosing interval
is equal to the administered dose
 DRUG ACCUMULATION…
Drug Accumulation during Multiple Dose Regimen
Dose =100 mg Dosing interval = t1/2 of the drug
No. of half
lives No. of doses
(Frequency
1 2 3 4 5 6 7 8
number)

0 100 Max -
1 50 Min 150
2 75 175
3 87.5 187.5
4 93.8 193.8
5 96.88 196.88
6 98.44 198.44
7 99.22 199.22 Max
This prediction of the amount of the drug in the body following repeated doses of a drug
8
in the above 99.61
example is based on the assumption that its elimination half-life Min
is constant
throughout the dosage regimen
 PRINCIPLE OF SUPERPOSITION
 An accepted plasma concentration profile at the steady state
can be devised with the aid of pharmacokinetic parameters
derived from single dose experiments based on the ‘principle of
superposition’
 The principle of superposition assumes that early doses of a
drug do not affect the pharmacokinetic of subsequent doses
 The basic assumptions are that the drug is eliminated by first
order kinetics and that the pharmacokinetics of the drug after a
single dose (first dose) are not altered for multiple doses
 Therefore, the blood level after the second, third, or nth dose will
overlay or superimpose the blood level attained after n-1th dose
 In addition, AUC (0 – α) following the administration of a single
dose equals the AUC (t1 – t2) during a dosing interval at
steady state
 PRINCIPLE OF SUPERPOSITION…
Simulated date showing blood level after administration of multiple
doses and accumulation of blood level when equal doses are
given at equal time intervals
Plasma Drug Concentration

AUC (t1 – t2)

Time (hours)
 PRINCIPLE OF SUPERPOSITION…
 Thus, the drug levels in plasma versus time data obtained with
a single dose is used to predict the drug levels in plasma after
multiple doses

 As the superposition principle is an overly method, it may be

used to predict drug concentrations after multiple doses given
at equal and unequal dosage intervals

 The predicted plasma concentration would be the total drug

concentration obtained by adding the residual drug
concentration obtained after each previous dose

 The principle of superposition can not be used in certain

situations, including, changing pathophysiology, saturation of
the drug carrier system, saturated protein binding, saturated
active secretion, enzyme induction and enzyme inhibition
 REPETITVE I.V. INJECTION – ONE COMPARTMENT

OPEN MODEL
Calculation of plasma drug concentrations following repetitive doses of a
drug using superposition principle requires preparation of a list of plasma
drug concentrations for each dose as shown in table
Dose No. Time Plasma drug doses level (mg/ml) Total
(hours)
1 2 3 4 5

1 0 0 0
1 21.0 21.0
2 22.3 22.3
3 19.8 19.8
2 4 16.9 0 16.9
5 14.3 21.0 35.3
6 12.0 22.3 34.3
7 10.1 19.8 29.9
3 8 8.5 16.9 0 25.4
9 7.15 14.3 21.0 42.5
10 6.01 12.0 22.3 40.3
11 5.06 10.1 19.8 35.0
4 12 4.25 8.5 16.9 0 29.7
13 3.58 7.15 14.3 21.0 46.0
14 3.01 6.01 12.0 22.3 43.3
15 2.53 5.06 10.1 19.8 37.5
5 16 2.13 4.25 8.5 16.9 0 31.8
17 1.79 3.58 7.15 14.3 21.0 47.8
18 1.51 3.01 6.01 12.0 22.3 44.8
19 1.27 2.53 5.06 10.1 19.8 38.8
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 Let us consider that a drug was repeatedly injected intravenously at a dose
of X0 with a dosing interval of ‘t’ hours
 The maximum concentration of the drug in plasma following a rapid i.v.
injection is equal to the dose divided by Vd of the drug

C0 = X 0 / Vd
 The concentration of the drug in plasma at any time t is given by

 Where K is the overall elimination rate

− Ktconstant
 C = C .e
The concentration of the drug 0 in plasma at the end of the first dosing
interval, , is given by

τ
0 − Kτ
C1 = C1 .e
τ
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
τ
 Where C is the concentration of the drug in plasma at the end of the first
dosing interval1 τ
0is zero time concentration for first dose

 C
The1zero time concentration of the drug in plasma following the second dose will
be

τ
 But, C =C +C
0
2 1
0
1
− Kτ
 Therefore,
C = C .e
1
τ 0
1
 Let R = then, the above equation can be written as
− Kτ
C = C .e
0
2
0
1 +C 0
1
− Kτ
e
C = C .R + C
0
2
0
1
0
1
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 The drug concentration in plasma at the end of the second
dosing interval is given by
τ 0 − Kτ
C = C .e
2 2 = (C R + C ) R
0
1
0
1
 Now, this procedure can be used for finding zero time
concentration (maximum drug concentration in plasma) and drug
concentration at the end of dosing interval (minimum drug
concentration in plasma) for each dose of the drug
τ
C = C + C = (C R + C ) R + C
0
3 2
0
1
0
1
0
1
0
1

τ
C = C R = [(C R + C ) R + C ]R
3
0
3
0
1
0
1
0
1
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 Since the plasma concentration at the beginning and end of the nth dosing interval
are given by the following series
 Beginning =
( n −1)
End =
C + C .R + C .R + ..........+ C .R
0
1
0
1
0
1
2 0
1


C R + C .R + C .R + ..........+ C .R
0
1
Since, R is always smaller
0 2 0 3
1 Rn becomes1smaller as n increases
than 1,
0
1
n

 Therefore, the high power terms in the above equations become negligible as ‘n’
increases and additional doses do not change the value of or significantly
 This explains why the plasma concentrations reach a plateau instead of continuing
to rise as more doses are given

Cn0 Cnτ
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 When n = ∞, the above equations become

Cmax = C / 1 − R 0
1

Cmin = Cmax.R = C R / 1 − R 0
1

 Hence, Cmax and Cmin are defined as the plasma concentration at the beginning and end,
respectively, of the nth dosing interval after the plateau has been reached (i.e., n = ∞)

 Thus, the maximum and minimum plasma concentrations on the plateau of a repetitive i.v.
dosing regimen can be calculated if the dosing interval ( ), the overall elimination rate
constant (K), and the initial plasma concentration (C0) are known

τ
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 An average steady state plateau drug concentration Cave , is obtained by dividing
AUC for a doing period by the dosing interval


C ave =
it should be remembered that C
[ AUC
is not
ave
] / τ t2
t1 arithmetic
the mean of Cmax and Cmin
because plasma drug concentrations decline exponentially
 The AUC (t1-t2) is related to the dose X0 divided by the total body clearance (Vd. K)

 Therefore,

[ AUC] = X 0 / Vd .K
t2
t1

Cave = X 0 / Vd .K .τ
 REPETITVE I.V. INJECTION – ONE COMPARTMENT
OPEN MODEL….
 Equations can also be expressed in terms of the amont of the drug in
the body

X max = X 0 / 1 − R X m in = X m a x.R = X 0 R / 1 − R
X ave = X 0 / K .τ
 Where, Xmax , Xmin , and Xavg are the maximum , minimum and average
amount of the drug in the body at the steady-state
 It is sometimes desirable to know the plasma drug concentration at
any time after the administration of ‘n’ doses of a drug
 The general expression for calculating this plasma drug concentration
is
Kτ
− n − Kτ − Kt
C = C (1 − e
t
n 0 /1− e )e
 REPETITVE I.V. INJECTION – ONE COMPARTMENT

OPEN MODEL….
τ
Where ‘n’ is the number of doses given and is the time after the nth dose
 At steady state approaches
n Kτ
zero and equation reduces to
−
e
∞ − Kτ − Kt
C = C0 (1 / 1 − e
n )e
Repetitive Extravascular Dosing – One Compartment Open
Model
 Although the equations become considerably more complex than for the
i.v. case, Cmax , Cmin , Cave can be calculated when the drug is administered
by an extravascular route
 The basic assumptions made in developing the equations for the
extravascular route are
 Drug absorption and eliminated processes follow first order kinetics
 The pharmacokinetic parameters such as Ka, K, Vd, and the fraction of the dose
absorbed (F) remain constant during multiple - dosing
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 The equation describing the plasma drug concentration – time profile
following a single dose of extravascular administration of the drug is given by

− Kt −k t
 C = [ K FX / V ( K − K )](e
a 0 d a th −e
a
If n fixed doses of the drug (X0) are administered at fixed time intervals )
(t), the
plasma drug concentrations following the n dose are given below

− nKτ − Kτ − Kt
C = K a FX 0 / Vd ( K a − K ){[(1 − e
t
n /1− e )e ]
− nK aτ − K aτ − K at
 −Whereas
[(1 − e /1− e )e ]}
is the concentration of the drug at time t, after nth dosing
 When ‘n’ is large (i.e., when the plasma concentrations reach a plateau), the
t
terms Cand
n becomes negligible

e − nKτ e − nK aτ
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
∞ −Kτ
C n = K a FX 0 / Vd ( K a − K )[( e Kt
/ 1 −e )
−(e −K a t / 1 −e −K aτ )]
 The above equation can be used to calculate the Cmax and Cmin values
on the plasma concentration plateau by substituting values for t which
correspond to the ‘peaks’ and ‘troughs’ in the C versus t curve
 Thus if t = tp (the time of peak concentration of drug in plasma),

Cmax = K a FX 0 / Vd ( K a − K )[( e Ktp / 1 − e −Kτ )

−K a tp −K aτ
− (e / 1 −e )]
 If t = 0 (the time at which another dose is to be given) the equation gives
Cmin

Cmax = K a FX 0 / Vd ( K a − K )[( 1 / 1 − e −Kτ ) − (1 / 1 − e −K aτ )]

 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 The mean plasma level at steady state Cave is obtained by applying the similar
method used for repeated i.v. injections

Cave = [ AUC] / τ t
or2
t1 Cave = FX0 / Vd Kτ
since
[ AUC] = FX0 / Vd K
t2
t1

Multiple Dose Regimen – Loading Dose

 The time required for the drug to accumulate to a steady state plasma level is
dependent mainly on its elimination half-life
 The time need to reach 95% Cave is approximately 5 half-lives of the drug
 for a drug with a half-life of 5 hours, it would take approximately 25 hours to reach
95% of Cave
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 In order to initiate a immediate therapeutic effect, an ‘initial dose’
also called ‘loading dose’ or ‘primary dose’ is administered to
achieve Cave

i.v. injections:
 As we know X ave = Cave .Vd = X 0 / K .τ
 Where X0 is i.v. dose, τ is dosing interval, Vd is the volume of
distribution of the drug and k is the elimination rate constant
 Therefore we should administer a loading dose X* just before the
administration of the maintenance dose X0
Kτ
 The amount present in the body is equal to X0/

τ
The amount of the drug present in the body after
= following and an i.v dose of X* is X ave
t
− Kτ
X ave = X * .e
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 The amount of the drug eliminated during this period must be
supplied in the form of a maintenance dose X0
 The amount of a the drug eliminated from a loading dose in
timeτ , is equal to the difference between the loading dose
τ
(X*) and the amount remained in the body after (Xave)
 Amount of the drug eliminated
= X * −X ave
= X * −X * e −Kτ
−Kτ
= X * (1 −e )

 The amount of the drug eliminated should be equal to the

maintenance dose, X0, to maintain the steady-state level
−Kτ
 Therefore, Maintenance X =
dose,
0 X * (1 − e )
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 And loading dose,
X * = X 0 /(1 −e −Kτ )
 In practice, the Cave, value for a particular drug is known
 The elimination rate constant (K), Volume of distribution (Vd)
and dosing interval are taken from the literature to calculate the
loading dose (X*), using the following equation
LodingDose X * = X ave / e −Kτ =C ave Vd / e −Kτ
 The ratio of loading to maintenance dose depends on the
dosing interval and the half-life of the drug and is equal to the
accumulation index, Rac
Rac = X * / X 0 =1 / 1 −e −Kτ
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
Extravascular Dosing
 In case of extravascular dosing, the fraction of the dose absorbed, F,
should be taken into consideration while calculating the loading dose
 Loading Dose

Maintenance Dose
X * =(C ave .Vd / e −Kτ ) / F

−Kτ
X = X * (1 −e ) / F Open Model
Multiple dose 0regimen – Two Compartment
 One compartment equations modified in minor ways apply to two
compartment systems with reasonable accuracy, when the distribution
phase after one dose is approximately complete before the next dose is
administered
 REPETITVE EXTRAVASCULAR DOSING– ONE
COMPARTMENT OPEN MODEL….
 Under these conditions, β may be substituted for K and Vdarea for
Vd, to adopt one compartment equations to two compartment
systems for rough approximations of the two compartment
parameters and plasma concentrations
For i.v. injections:
C ave = X 0 / βVdarea τ
Loading Dose
=C ave .Vdarea / e −βτ

For extravascular dosing:

C ave =FX 0 / βVdarea τ
Loading Dose
=(C ave .Vdarea / e −βτ ) / F

 The accumulation ratio of the drug Rac is the ratio of loading

R =
and maintenance
ac ( X * / X ) −(1 / 1 −e −βτ )
doses
0