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