3.
3
Introduction
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
4.
4
In Designing dosage
regimen the two major
parameters that can be
adjusted in developing a
dosage regimen are…
1) The Dose size – The qty.
of Drug administered.
Greater dose size
greater fluctuation btw
Cssmax, & Cssminand greater
chance of toxicity
2) The Dosing frequency –
The time interval
between Doses.
5.
5
Design of dosage regimen from plasma
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 :
זז max = 2.303 log ( Cupper / Clower )
KE
Where KE = 0.693/t1/2
6.
6
זז max= 3.32 t1/2 log ( Cupper / Clower )
Mostly dosing interval selected is always smaller than זז max
the maximum maintenance dose X0maxcan be expressed as
X0max= Vd ( Cupper - Clower )
F
After the convenient dosing interval זז ,, smaller thansmaller than זז max has
been selected, maintenance dose is given as :
X0 = Css,av =
Xo max
זז maxmax
זז
( Cupper / Clower )
2.303 log ( Cupper / Clower )
7.
7
Multiple dosing
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.`
8.
8
Effect of multiple doses
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.
9
Effects of dose and dose frequencyEffects of dose and dose frequency
Increase in doseIncrease in dose
– Increase in CIncrease in Cmeanmean
– Larger difference between CLarger difference between Cmaxmax and Cand Cminmin
– Increased risk for side effects for drugs with smallIncreased risk for side effects for drugs with small
therapeutic windowstherapeutic windows
Increase in frequencyIncrease in frequency
– Increase in CIncrease in Cmeanmean
– Larger inconvenience for patientLarger inconvenience for patient
10.
10
Loading Dose
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.
XXo,o,L =L =
CCss,avss,av VVdd
FF
11.
11
When Vd is not known then loading dose may be
calculated as
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.
XXooLL
XX00 (1 –e(1 –e –Ka–Kaזז
)) (1 – e(1 – e –Ke–Ke זז
)
11
=
XXo,o,LL
XX00
=
1 – e1 – e -Ke-Keזז
11
= R= Racac
12.
12
Maintenance Dose
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 -kז
)
Loading dose =
maintenance dosemaintenance dose
1 – e1 – e -K-K זז
13.
13
The ratio of loading dose
to maintenance dose
(X0L/X0) is called as dose
ratio
When ז = t1/2 the dose ratio
=2.0
When ז > t1/2 the dose ratio
< 2.0
when ז < t1/2 the dose ratio
>2.0
14.
14
Accumulation 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.
16.
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
/2X0
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.
17
The maximum & minimum values of X i.e. Xss,max & Xss,min
approach respective asymptotes at plateau.
Plateau Xss,min = 1X0 (amt of drug in body after first dose ) Xss,max =
2X0 ( equals twice the first dose)
Also (Xss,max- Xss,min) = X0
Xss,max / Xss,min = 2
All this applied only when ז = t1/2
18.
18
When ז < t1/2 , 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:
=Rac
1
1-e -KE ז
19.
19
References
‘Applied Biopharmaceutics & Pharmacokinetics’
by Leon Shargel & Andrew B. C. Yu, 4th
Edition
‘Biopharmaceutics & Pharmacokinetics’
A Treatise, D. M. Brahmankar & Sunil B. Jaiswal
‘Clinical Pharmacokinetics, Concepts &
Application’, 3rd
Edition,
by Malcom Rowland & Thomas N. Tozer, Lea & Febiger
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