Population Pharmacokinetics of Oral Clopidogrel in South Indian Cardiovascular Patients Using Nonmem

Objective: The objective of the study was to perform a Non linear mixed-effects analysis of the pharmacokinetics of clopidogrel, to study the effect of covariates like age, body surface area and creatinine clearance on the population pharmacokinetics of clopidogrel in South Indian Cardiac patients. Methods: A simple, rapid and sensitive isocratic HPLC-UV method for detection and quantification of clopidogrel in plasma had been developed. Intra-and inter-assay variations were <1and <2% respectively. Recovery of clopidogrel was 98-99%. Total 281 blood samples for clopidogrel plasma concentration measurements following a single 75 mg and150 mg /day dose of clopidogrel were obtained from 75 subjects having age in between 18-70 years. The population PK model was built using NONMEM 7.2. The FO and FOCE methods were used to estimate base and covariate models for clopidogrel. Results: One-compartment model with first-order absorption and elimination (ADVAN 2 TRANS 2) was best fit to the plasma concentration-time data of clopidogrel. A combined error model was best described the pattern of residual and between subject variability. The final model estimates of CL and V estimated by FOCE method were 7.6 L/h and 12.6 L. Discussion: There were no past reports on PopPK of clopidogrel in India. With covariate models, no significant decrease was observed in OFV, intra and intersubject variability when compared to the base model. The model that best describe the data following the FOCE method was: Clearance (CL) = θ1*EXP (ETA (1)) and Volume (V) = θ2*EXP (ETA (2)). No covariates were found as informative for clopidogrel. Conclusion: The POPPK model for clopidogrel has been developed, No covariate has been found to be a factor that affects the individual variability in pharmacokinetics of clopidogrel.