Population Pharmacokinetics Of Clopidogrel In Patients After PCI

OBJECTIVE To establish a population pharmacokinetic model of clopidogrel based on the concentration data of its carboxylic acid metabolites in patients after PCI,administration information?usage,dosage,time of administration?,blood collection time and clinical physiological and biochemical indicators,so as to provide evidence for the safe and effective use of clopidogrel in clinic.METHODS The monitoring data and clinical data of the concentration of clopidogrel carboxylic acid metabolites?CLPM?in patients undergoing PCI from June 2014 to September 2015 were collected.The concentration of CLPM was determined by high performance liquid chromatography?HPLC?.A one-compartment pharmacokinetic model of clopidogrel was established by using NONMEM method.The effects of different clinical factors,including age,sex,physiological and biochemical indexes,combined drug use,combined disease,gene polymorphism and other covariates on the pharmacokinetic parameters of clopidogrel were investigated.The final pharmacokinetic model of clopidogrel was established by stepwise regression method,and the model was evaluated.RESULTS 1.A total of 185 patients who met the inclusion and exclusion criteria were collected.The blood concentration of stable clopidogrel carboxylic acid metabolite was185 times.The clinical data of 185 patients were collected,including age,sex,blood routine,liver function,renal function,uric acid,fasting blood sugar,myocardial enzymes,blood lipids,anticoagulant,combined drug use?ACEI/ARB,CCB,PPI,beta blocker?.Statins,complications?hypertension,diabetes?and 19 important transporters and metabolic enzymes related gene loci data.Other covariates,such as height,weight,postprandial blood sugar and glycosylated hemoglobin,were not included in this study because of the high proportion of missing covariates.2.A population pharmacokinetic model of clopidogrel was established based on the above data.The typical population values of absorption rate constant?KA?,apparent clearance?CL?and apparent distribution volume?V?were 1.2 h^-1,4.92 L·.h^-1 and 396 L,respectively,and the objective function value?OFV?was-183.97.3.It was found that RBC,RDW,GLU,TBI,IBIL,CYP3A5,CYP2C19*3 slightly affected the apparent clearance rate of clopidogrel carboxylic acid metabolites by screening the covariates,but had no statistical significance,so they were not included in the covariate model.Therefore,no covariates were found that could significantly reduce the individual variation of pharmacokinetic parameters.The basic one-compartment model was the final model.It was proved that the model was stable and effective,and could predict the steady Valley concentration of carboxylic acid metabolites after clopidogrel administration,so as to guide the optimization of drug delivery scheme.CONCLUSION A population pharmacokinetic model of clopidogrel in patients after PCI was established by using NONMEM software based on the collected and measured drug concentration data and clinical data.The parameters such as absorption rate constant?KA?,apparent clearance rate?CL?and apparent distribution volume?V?were1.2 h^-1,4.92 L.h^-1 and 396 L,respectively.This model can be used to estimate the blood concentration of clopidogrel in patients with known dose.However,no covariates affecting pharmacokinetic parameters have been found in this study,which needs to be further investigated in order to provide more references for clinical individualized antiplatelet therapy.