title: Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy.
abstract: OBJECTIVE
  Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM(®) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity.
  
  
  METHODS
  Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples.
  
  
  RESULTS
  A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times.
  
  
  CONCLUSIONS
  A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures.
authors: Department of Biopharmaceutics and Clinical Pharmacy, University of Jordan, Amman, Jordan.
authors: A M
authors: AM
authors: Yousef
authors: M
authors: M
authors: Melhem
authors: B
authors: B
authors: Xue
authors: T
authors: T
authors: Arafat
authors: D K
authors: DK
authors: Reynolds
authors: S A
authors: SA
authors: Van Wart
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D000077144:Clopidogrel; D006801:Humans; D007597:Jordan; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine