Non Linear Pharmacokinetics

Non linear pharmacokinetics, Biopharmaceutics

1. Non-Linear Pharmacokinetics Presented by: Akash Vikal M.Pharm ( Pharmaceutics) 2 nd Semester, 1 st Year Presented to :- Dr. Dilpreet singh HOD – Regulatory affairs ISF COLLEGE OF PHARMACY

2. Non-Linear Pharmacokinetics The kinetics of a pharmacokinetic process in some instances may changes from primarily first order to primarily zero order with the increase in dose. Sometimes a mixture of both the reactions is seen and hence they said to have followed mixed order kinetics. As the deviation is seen from the original linear pharmacokinetics, the rate process of such drugs is called as non-linear kinetics . They are also known as Dose-dependent pharmacokinetics.

3. Causes of non linearity Saturation of enzymes in process of drug ADME Pathologic alteration in drug ADME .

4. Non-linearity may occur by one of the following factors namely drug absorption, distribution, metabolism and excretion. Drug Absorption : In drug absorption, non-linearity may arise: Saturation of carrier mediated transport . Saturation of pre-systemic gut wall or hepatic metabolism. Saturation of solubility.

5. II. Drug Distribution : In drug distribution, non-linearity may arise due to: Saturation of binding sites on plasma proteins . There is specific number of binding sites for a particular drug on plasma proteins. Therefore as the concentration of the drug is raised, simultaneously unbound fraction will be raised. Saturation of tissue binding sites : saturation of tissue storage sites may occur due to multiple dosing or with a large single bolus dose

6. III. Drug Metabolism : Capacity limited metabolism is clinically most important in nonlinear kinetics as the minute changes in the administered dose can produce large variations in plasma concentration at steady state. The non-linearity in metabolism of the drug is due to: Capacity limited metabolism due to enzyme or cofactor saturation Enzyme induction : On repetitive administration over a period of time, a decrease in peak plasma concentration is observed.

7. IV. Drug Excretion : Two saturable active process in renal excretion of a drug are: Active tubular secretion : as the carrier system is saturated, a decrease in renal clearance is seen. Active tubular reabsorption : as the carrier system is saturated, an increase in renal clearance is seen

8. MICHAELIS-MENTEN EQUATION : Non-linear pharmacokinetics can be best described by Michaelis- Menten Equation. where, dc/dt : rate of decline in drug concentration with time. Vmax : theoretical maximum rate of process. Km : Michaelis constant.

9. Linear vs. Non-linear Pharmacokinetics LINEAR PHARMACOKINETICS Dose independent. ADME obeys first order kinetics. PK parameters (CL, V, Ka, t1/2) are constant. AUC is directly proportional to the dose. Conc. vs time profile is superimposable for all doses. NON-LINEAR PHARMACOKINETICS Dose dependent. At least one of the ADME process is saturable. ≥1 PK parameters are dose dependent. AUC is disproportional to the dose. Conc. vs time profile is not superimposable for different doses.