Residual Method (Feathering Technique)

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Residual method with application of pharmacokinetic in now drug development

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Feathering Technique and Application of Pharmacokinetics in New Drug Development:

Feathering Technique and Application of Pharmacokinetics in New D rug D evelopment Guided By: Prepared By: Ms. Krupa Thula Rucha Patel Asst. Prof M.Pharm Sem I Dept. of QA QARA L.J. INSTITUTE OF PHARMACY 1

CONTENTS:

Absorption Rate Constant Application of Pharmacokinetics 1. In New Drug Development # Absorption # Distribution # Plasma Half-Life # Metabolism 2. In New Drug Delivery System CONTENTS 2

Absorption Rate Constant(1):

When a drug is administered by extravascular route, absorption is a prerequisite for its therapeutic activity. The absorption rate constant can be calculated by the method of residuals. The technique is also known as feathering, peeling and stripping. Absorption Rate Constant (1) 3

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It is commonly used in pharmacokinetics to resolve a multiexponential curve into its individual components. For a drug that follows one-compartment kinetics and administered extravascularly, the concentration of drug in plasma is expressed by a biexponential equation. C [e - K E t – e -K a t ] (1) If K a FX 0 / V d (K a -K E ) = A, a hybrid constant, then: C = A e - K E t – A e -K a t (2)   4

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During the elimination phase, when absorption is almost over, K a << K E and the value of second exponential e -K a t approaches zero whereas the first exponential e - K E t retains some finite value. At this time, the equation (2) reduces to: (3) In log form, the above equation is: Log C − = log A - (4)   5

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Where , C − = back extrapolated plasma concentration values A plot of log C versus t yield a biexponential curve with a terminal linear phase having slope –K E /2.303 Back extrapolation of this straight line to time zero yields y-intercept equal to log A . 6

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Plasma Conc.-time profile after oral administration of a single dose of a drug 7

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Subtraction of true plasma concentration values i.e. equation (2) from the extrapolated plasma concentration values i.e. equation (3) yields a series of residual concentration value C τ . (C − - C) = C τ = A e -K a t (5) In log form , the equation is: log C τ = log A - (6)   8

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A plot of log C τ versus t yields a straight line with slope -K a /2.303 and y-intercept log A . Thus, the method of residual enables resolution of the biexponential plasma level-time curve into its two exponential components. The technique works best when the difference between K a and K E is large (K a /K E ≥ 3). 9

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Application of Pharmacokinetics 10

Application of Pharmacokinetic:

In new drug development In new drug delivery system Application of Pharmacokinetic 11

Application in New Drug Development(2):

In  vitro studies are very useful in studying the factors influencing drug absorption and metabolism. These studies are useful for the new drug development. Application in New Drug Development (2) 12

Absorption:

Two physicochemical factors that effect the both extent and rate of absorption 1. L ipophilicity 2. Solubility Increase in the lipophilic nature of drug results in increased in oral absorption Absorption 13

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Example: Biophosphonates drug with poor lipophilicity will be poorly absorbed after oral administration . Absorption of the barbiturates compounds increased with increasing lipophilicity. Higher the lipophilicity of a drug the higher its permeability and the greater its metabolic clearance due to first pass effect. Solubility is also an important determinant in drug absorption. Eg . HIV protease inhibitors are basically lipophilic and poorly soluble resulting in poor bioavailability. 14

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The solubility of the HIV protease inhibitors can increased by incorporating a basic amine in to the back bone of this series. Pro drugs are developed to improve oral absorption Eg . Pivampicillin, Becampicillin are the prodrugs of ampicillin. 15

Distribution:

Lipophilicity of the drug affects the distribution. Higher the lipophilicity of a drug the stronger its binding to protein & the greater its distribution. Eg. Thiopental & polychlorinated insecticides. These drugs are highly distributed and accumulate in adipose tissue. Distribution 16

Plasma Half-Life:

Administration of a drug with a short half life requires frequent dosing and often results in patient incompliance. Half life determined by distribution & elimination. The prolongation of half life can be achieved by increasing the volume of distribution & decreasing the clearance. Plasma Half-Life 17

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Latter appear to be easier i.e. to modify the chemical structure to slow down a drug clearance than to increase its volume of distribution E.g. The addition of an alkyl amine side chain linked to the dihydropyridine 2-methyl group yield amlodipine with a lower clearance which has an improved oral bioavailability and plasma half life without loss of antihypertensive activity. 18

Metabolism:

Metabolism of drugs is usually very complex, involving several pathways and various enzyme system. In some cases all the metabolic reactions of a drug are catalyzed by a single isoenzyme, where as in other cases a single metabolic reactions may involve multiple isoenzymes or different enzyme system . Metabolism 19

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E .g. Oxidative metabolic reactions of indinavir are all catalyzed by a single isozyme in human liver microsomes. Two isozymes cyt p-142 & cyt p-344 are involved in human liver microsomes 20

Application in New Drug Delivery System(2):

To understand process of absorption, distribution and elimination after administration of drug , which affects onset and intensity of biological response. To access plasma drug concentration response to given dose which is now considered as more appropriate parameter than  intrinsic pharmacological activity . Application in New Drug Delivery System (2) 21

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In design and utilization of in vitro model system that can evaluate dissolution characteristics of new compound formulated as new drug formulations . In design and development of new drug and their appropriate dosage regimen. In safe and effective management of patients by improving drug therapy. To understand concept of bioavailability which has been used to evaluate and monitor in vivo performance of new dosage forms and generic formulations. 22

Reference :

D. M. Brahmankar and Sunil B. Jaiswal, Biopharmaceutics and Pharmacokinetics , V allabh P rakashan, Page no: 278-279 N.K.Jain, Advances in Controlled and Novel D rug D elivery S ystem , CBS P ublishers and D istributors, F irst edition 2005 , Page no: 176-185 23 Reference

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Thank You 24

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