1

Kinetics of
multiple dosing
https://www.youtube.com/watch?
v=Tsp9t3D2TL0
 2

1. Introduction
2. Multiple Dosing
3. Designing of Dosage
regimen
4. Concept of Loading Dose.
5. Maintenance Dose.
6. Accumulation Index.
7. References
 Introduction 3

Definition :- Dosage regimen is defined as the Manner in

which a drug is taken.
For successful therapy, design of an optimal multiple dosage
regimen is necessary.
Multiple dosage regimen:- is defined as the manner in which the
drug is administered in suitable doses by suitable route, with
sufficient frequency that insures maintenance of plasma conc.
within therapeutic window for entire period of therapy.
In designing a dosage regimen:-
• All p’kinetic parameters of the drug remain constant during the
course of therapy once the Dosage regimen is established.
• The calculations are based on one- compartment model which
can also applied for two- compartment models. β
KE
Vd,ss Vd
 In designing dosage regimen
the two major parameters that 4
can be adjusted in developing
a dosage regimen are…
1) The Dose size – The qty. of
Drug administered.
Greater dose size
greater fluctuation btw Csmax,
& Csmni and greater
chance of toxicity
2) The Dosing frequency – The
time interval between
Doses.
 Design of dosage regimen from plasma 5
concentration :

If the Vd and clearance or half life of the drug is known, then

dosage regimen can be design to maintain the drug conc. in
the therapeutic range.
Maximum dosing interval which ideally depends upon the
therapeutic index and elimination half life of the drug can be
expressed as :

Cmax= 2.303 log ( Cupper/ Colwer )

KE

Where KE= 0.693/t1/2

 6
‫ ז‬max= 3.32 t1/2 log ( Cupper / Clower )
Mostly dosing interval selected is always smaller than ‫ ז‬max
the maximum maintenance dose X0maxcan be expressed as

X0max = Vd ( Cupper - Clower )

 F
 After the convenient dosing interval ‫ ז‬, smaller than ‫ ז‬maxhas been
selected, maintenance dose is given as :

Xo max ( Cupper / Clower )

X0 = ‫ז‬
‫ ז‬max Css,av = 2.303 log ( Cupper / Clower )
 Multiple dosing 7

For chronic diseases, there is necessity of multiple dosing

i.e. administration of drugs in number of frequencies.
On continuous steady administration of a drug, plasma
concentration will rise fast at first then more slowly and
reach a plateau, where:
Rate of administration = Rate of elimination
( steady state is achieved )
Therefore, at steady state:
Dose (Rate of Administration) = Clearance x Plasma
conc.
Or
If you aim at a target plasma level and you know the
clearance, you can calculate the dose required.`
 Effect of multiple doses 8

If the plasma concentration prior to next dose is >0

concentration and elimination is of first order, then plasma
concentration will increase Increase in elimination rate
and eventually steady state.

– For first order elimination kinetic the time to obtain steady

state is dependent only of the half time of the drug
– The steady state concentration is determinated by dose
(D) and dose frequency
 9

Effects of dose and dose frequency

Increase in dose
– Increase in Cmean

– Larger difference
between Cmax and

Cmni
– Increased risk for side effects for drugs with small
therapeutic windows
Increase in frequency
 Loading Dose 10

Concept of loading dose

For drugs with long half-lives, the time to reach steady

state might be long. It takes about 5 half- lives to reach
steady state.
In a such cases the plateau can be achieved by
administering a dose that gives the desired steady- state.
Such an initial/ first dose is called as Loading dose.
Vd
Xo,L = Css,av
F
When Vd is not known then loading dose may be
11

calculated as

XoL 1
X0 = (1 –e –Ka‫( )ז‬1 – e –Ke ‫) ז‬
The above eq. is applied when Ka >> Ke & drug is
distributed rapidly.
But in case of I.V. route the absorption is very fast therefore ,
absorption phase is neglected then above eq.
Xo,L 1
X0 = ac
= R
1–e -Ke‫ז‬
 Maintenance Dose 12

After the loading dose is given the another dose (I.V) is

given to maintain the steady- state drug conc. Or plateau.
Such dose is known as maintenance dose.
i.e. maintain the response of drug by replacing drug lost
during dosing interval.
Maintenance dose = loading dose x ( 1- e -k‫)ז‬

Loading dose = maintenance dose

1 – e -K ‫ז‬
 13

The ratio of loading dose

to maintenance dose
(X0L/X0) is called as
dose
ratio
When ‫ = ז‬t1/2the dose ratio
=2.0
When ‫ > ז‬t1/2the dose ratio
< 2.0
when ‫ < ז‬t1/2the dose ratio
>2.0
 Accumulation 14
Index
 In case of multiple dosage regimen (drugs are frequently
administered) in such a cases the 1st drug conc. remaining
in a body after certain time, is added to the next dose, this
condition is known as ‘Accumulation’
 The accumulation occurs because previous doses has not
been removed completely from body.
 After some time the rate of absorption is equal to rate of
elimination i.e. conc. of drug in plasma approaches to a
constant value this condition is called as steady- state,
plateau/ infusion equilibrium.
15
 16
Consider the Amount of drug in the body-time profile as
shown in the Graph.
After admin of first dose X0 = 1X0
At next dosing interval when X = ½ X0, amt of drug remaining
in the body
Admin of next i.v. dose raises the body content to X = X0 + 1/2
X0

As the amount of drug in the body rises gradually due to

Accumulation, the rate of elimination also rises proportionally
until a steady-state or Plateau is reached.
 17
The maximum & minimum values of X i.e. Xs,max& Xssm, in

approach respective asymptotes at plateau.

Plateau Xssm, in= 1X0 ( amt of drug in body after first dose )
Xss,max =
2X0 ( equals twice the first dose)

Also (Xss,max - Xss,min) = X0

=2
Xss,max / Xss,min

All this applied only when ‫ = ז‬t1/2

 18

When ‫ < ז‬t1/2 , the degree of Accumulation is greater & vice-

versa.
Thus, the extent to which a drug accumulates in the body
during multiple dosing, is a function of dosing interval &
elimination half life & is independent of dose size.
The extent to which a drug will accumulate with any dosing
interval in the patient can be derived from information
obtained with a single dose and is given by accumulation
index Rac as:
1
Rac
= 1-e -KE ‫ז‬