MULTIPLE DOSING

K.PRADEEP KUMAR
M.PHARM (PHARMACEUTICS)

03-03-2011 1
 CONTENTS

Ø Dosage regimen
Ø Drug accumulation
Ø Principle of superposition
Ø Multiple dosing with respect to I.V.
Ø Multiple dosing with respect to Oral route.
Ø Concept of loading dose, maintenance dose,
Ø References.
•
 INTRODUCTION
• INTRODUCTION
A single dose may provide an effective

treatment. But the duration of

illness is longer than the therapeutic
effect produced by a single dose. In
such cases drugs are required to be
taken on a repetitive basis over a
period of time.
•
 C o n tin u e
…


 The multiple dosing achieves and

maintains drug concentration in
plasma or at the site of action that
are both safe and effective
•


 Two major parameters that can be

adjusted in developing a dosage regimen
are:
1.The dose size :- It is the quantity of the
drug administered each time.


2. Dose frequency :- It is the time interval



between doses.
1.
•
 DRUG ACCUMULATION
A)Drug accumulation during multiple
dosing: following the 1st dose, if
the 2nd dose is given early enough
so that not the entire 1st dose is
eliminated then the drug will start
accumulating and we will get
higher concentration with the 2nd
and 3rd dose.



B) steady state during multiple

dosing:
 The suitable amount of dose and
identical dosing interval leads to
steady state at which the mass of
drug administered or absorbed is
equal to the mass of drug eliminated
•
 Accumulation Index

C ss max
Steady state
Plasma drug conc.

X0+1/2X0

Css min

X0+1/4 X0
1/2X0

Time[h]
8
 No.of doses
no.of ½ 1 2 3 4 5 6 7 8
lives
0 100 max
1 50 min 150
2 75 175
3 87.5 187.5
4 93.8 193.88
5 96.88 196.88
6 98.44 198.44
7 99.22 192.22
8 99.6

10
•TheThe extent
extent toto which
which a drug
a drug accumulates
accumulates inin
thethe body
body is is a
a function
function
of its dosingofinterval
its dosing
andinterval and elimination
elimination of half-life
of half-life and is
and is independent
independent of dose size.
of dose size.
•
•The
The extent
extent toto which
which any
any drug
drug accumulate
accumulate with
with any
any dosing
dosing
interval
interval in ainpatient
a patient
cancanbe be derived
derived from
from information
information obtained
obtained
with a singlewith
dosea and
single dose and
is given is given by accumulation
by accumulation index Rac as :
index Rac as :

•
1
Rac = (1 – e-K Et)
 Principle of superposition

 It assumes that the early doses of drug do not affect the

pharmacokinetics of the sub sequent doses
 The basic assumptions are that the drug is eliminated by
1st order kinetics and that the pharmacokinetics of the
drug after a single dose are not altered for multiple
doses.
 Therefore, the blood levels after 2nd ,3rd or nth dose will
superimpose the blood levels attained after the (n-1)th
t2

 [AUC]∞0 of single dose = [AUC] t1 during a dosing interval at

steady state


11
• An equation for the estimation of the time to
reach one half of the steady state plasma
levels or the accumulation half life


accumulation t1/2 = t1/2 [1+3.3 log k /k -k]
a a
For iv administration, a is very rapid(approaches∞); k is


very small in comparison to ka



 ... t½=t½ [1+3.3 log ka/ka ] ... log 1=0



 Accumulation t½ = elimination t½
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 Repetitive iv injection
 On repeated drug administration,
the plasma concentration will be
added upon for each dose interval
giving a steady state


 Calculation of plasma drug

concentration is done using
superposition principle
•
14
• Dose =Xo
• Dosing interval of t hours
• Cmax = Xo/Vd (1)
• The concentration of drug in plasma at any time t
is given by C= Cmax .e-Kt (2)
• K=overall rate constant
• The concentration of drug in plasma at the end
of first dosing interval Ʈ , is given by C1t=C01. e-
K Ʈ (3)
• Where C1 Ʈ =concentrtion of the drug in plasma at
the end of first dosing interval of Ʈ
15
• C10 = zero time concentration for first dose
• The zero time concentration of the drug in
plasma following the second dose will be
C 0 =C1 Ʈ + C10 (4)
2
C1
 Ʈ = C10 . e-K Ʈ (5)
C20
 =C10 . eK Ʈ + C10 (6)

Let r = eK Ʈ then the above equation as be
written as
C 0 =C10 r + C10 (7)
2

16
• The drug concentration in plasma at the end of
the second dosing interval is given by
 C2Ʈ = C20 .e-K Ʈ = (C10r+C10)r (8)
 Now this procedure can be used for finding zero time
concentration & drug concentration at the end of dosing
interval for each dose of the drug.


 C30 = C2Ʈ + C10 = (C10r+C10)r+C10 (9)

 C3Ʈ = C30r=[(C10r+C10)r+C10]r (10)

... The plasma concentrations at the beginning & end of nth
dosing interval are given by the fallowing series


17
• Beginning= C10+C10r+C10r2+…………….+C10r(n-1)
(11)
• End = C10r+C10r2+C10r3+…………+C10rn (12)
• r<1, as n increases rn becomes smaller
• When n=∞ equation 11,12,becomes
• Cmax =C1/1-r= X0/Vd(1- e-KƮ ) (13)
• Cmin =Cmax .r
• An average study state concentration Cav is obtained by dividing
AUC for dosing period by the dosing interval
• Cav =[AUC]t2 t1 /Ʈ
• Plasma drug concenration at any time tCn=C0(1-e-nkƮ /1-e-kƮ ).e-kƮ
• N=no.of doses is time after nth dose. At steady state e-
nkƮ approaches zero ...C ∞=C (1/1-e-kƮ ) e-kƮ
n 0
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 Repetitive extra vascular dosing

• Drug absorption and elimination processes follow first order kinetics

• The pharmacokinetic parameters such as ka,k,vd & fraction of dose
absorbed(F) remain constant during multiple dosing
• The plasma drug concentration time profile following a single dose
is given by C =kaFX0/Vd(ka-k) (e-KƮ - e-KaƮ ) (14)
• If n fixed doses of drug X0are administered at fixed time
intervals(t),the plasma concentrations fallowing the nth dose are
given by
• Cn∞ = kaFX0/Vd(ka-k) [(1/1- e-KƮ ) e-KƮ (1/1- e-KaƮ )e-KƮ (15)
• The term tp(peak concentration of during in plasma after
single dose) is given by tp= (2.303/ka-k) log ka/k
(16)
•
•
19
• When t = tp
 2.303 log [ Ka(1- e-kƮ )]
 (Ka-k) [k(1- e-kƮ )]


 If t=tp from the equation 15 the Cmax is given as

 FX0 [( 1 ) e-ktp

Vd (1- e-kƮ )
 If t =Ʈ from the equation 15 Cmin is given as
 Cmin =KaFX0/Vd(Ka-k) [1 / 1-e-k ]e-kt
 Cave =FX0/Vd.KƮ

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 Loading Dose
• A drug dose does not show therapeutic activity unless it
reaches the desired steady state.
• It takes about 4-5 half lives to attain it and therefore time taken
will be too long if the drug has a long half-life.
• Therapeutic effect can be reached immediately by
administering a dose that gives the desired steady state
instantaneously before the commencement of maintenance
dose X0.
• Such an initial or first dose intended to be therapeutic is called
as priming dose or loading dose.
•
 Calculation Of Loading
I.V
Dose
Maintenance dose

X = X* (1-ekƮ )
0


Loading dose,
X* = X /(1-e-kƮ)
0
 Dose ratio = X*/X0


Extra vascular dosing maintenance dose

X* = c -kƮ X0=X*(1-e-kƮ)
av . Vd /e
 F

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 Calculation Of Loading
Dose
• When T > t1/2 dose ratio is smaller than 2.0
• When T< t1/2 dose ratio is greater than 2.0
•
• If the loading dose is not optimum either too low or too high,
the steady state is attained within a 4-5 half lives in a
manner similar to when no loading dose is given.


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 Dose ratio >2

loading dose X0,L

maintenance dose X0
X X X X
T 0 T 0 T T T
0 0

Dose ratio 2

MSC
Cp

MEC

dosing interval in hrs

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 Conclusion

• The successive administration of an

optimum dosing size and at an
identical dosing frequency that
shows minimum therapeutic
concentration results in produces
acute or required prolonged effect

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 Reference

• Biopharmaceutics And Pharmacokinetics A Treatise,

Brahmankar.
• “Text Book Of Biopharmaceutics & Pharmacokinetics”,
• By V.Venkateshwarlu
• Different website sources , g books
• ‘Applied Biopharmaceutics & Pharmacokinetics’
 by Leon Shargel & Andrew B. C. Yu, 4th Edition
• ‘Clinical Pharmacokinetics, Concepts & Application’, 3rd
Edition,
 by Malcom Rowland & Thomas N. Tozer, Lea & Febiger
•

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THANK YOU

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