Population Pharmacokinetic/ Pharmacodynamic Modeling of Clopidogrel in Korean Healthy Volunteers and Stroke Patients


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Abstract

Population pharmacokinetic (PK) and pharmacodynamic (PD) modeling of clopidogrel was developed from pooled data from healthy volunteers (n = 44) and stroke patients (n = 35). The PK modeling used plasma concentrations of the clopidogrel metabolite (SR26334), and the PD modeling used platelet aggregation. The models were developed using NONMEM and evaluated via visual predictive check (VPC). Data were analyzed by 2-compartment modeling with Erlang's absorption and first-order elimination. There was no statistically significant covariate for each model parameter. The typical point estimates of PK were ktr (identical transfer rate constant) = 5.97 h-1, ke (elimination rate constant) = 0.126 h-1, kd (distribution rate constant) = 0.212 h-1, V2 (volume of central compartment) = 21.0 L, and V3 (volume of peripheral compartment) = 38.8 L. The typical point estimates of PD were kin (input rate) = 27.9 h-1, Emax (maximum effect on input rate) = 0.292 h-1, EC50 (median effective concentration) = 0.00629 ng/mL, and BASE (predose aggregation) = 66.7%. The final model was used to estimate individual parameters using patient data and showed good predictions using VPC.

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