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Dosage Regimen

Presented By Shah Vrushank N.

 Introduction
Multiple Dosing Designing of Dosage regimen Concept of Loading Dose. Maintenance Dose. Accumulation Index. References

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 pkinetic 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. KE Vd,ss Vd
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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, & Cssmin and greater chance of toxicity 2) The Dosing frequency The time interval between Doses.
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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 :
max = 2.303 log ( Cupper / Clower )

KE
Where KE = 0.693/t1/2
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 max = 3.32 t1/2 log ( Cupper / Clower ) Mostly dosing interval selected is always smaller than max the maximum maintenance dose X0max can be expressed as X0max = Vd ( Cupper - Clower )

F After the convenient dosing interval , smaller than max has been selected, maintenance dose is given as : X0 = Xo max max Css,av =
( Cupper / Clower ) 2.303 log ( Cupper / Clower )
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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.`
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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

 Effects of dose and dose frequency Increase in dose Increase in Cmean Larger difference between Cmax and Cmin Increased risk for side effects for drugs with small therapeutic windows

Increase in frequency Increase in Cmean Larger inconvenience for patient

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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.

Xo,L =

Css,av Vd F

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 When Vd is not known then loading dose may be

calculated as
X oL X0

(1 e (1 e Ke ) Ka 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 = Rac = X0 1 e -Ke
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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 -k) maintenance dose
Loading dose =

1 e -K

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 The ratio of loading dose

to maintenance dose (X0L/X0) is called as dose ratio When = t1/2 the dose ratio =2.0 When > t1/2 the dose ratio < 2.0 when < t1/2 the dose ratio >2.0
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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.

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 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 = 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.
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 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 = t1/2

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 When < 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-e -KE
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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, Application, 3rd Edition,

Concepts

&

by Malcom Rowland & Thomas N. Tozer, Lea & Febiger www.google.com

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