The Study Of The Population Pharmacokinetic Model Of The Active Metabolite Of Oxcarbazepine In Chinese Epileptic Patients

Chapter One Simultaneous Determinationof Oxcarbazepine and Its Metabolite MHD in Human Plasma by HPLCObjective To establish a HPLC method for the simultaneous determination of OXC and active metabolite(MHD)in human plasma.Methods The SHIMADZU C18(150mm×4.6mm,5um)was used,mobile phase consisted of methanol-water(44::56),flow-rate was 1.0ml/min at 25?,detection wavelength was 240 nm.Phenobarbital was used as intemal standard.Plasma sample through the column after junior.Results The method was found to be linear over the concentration ranges(OXC 0.625~50ug/ml and MHD 0.625~50ug/ml).The extraction recovery of low,middle and high concentration OXC was82.52%,84.38% and 86.97% respectively,the method of extraction was 98.57%,101.6%,92.85%,the intra-RSD was 3.90%~6.14%,and inter-RSD was 3.25%~7.06%.The extraction recovery of low,middle and high concentration MHD was 83.65%,85.46% and 88.84% respectively,the method of extraction was 97.68%,100.6%,94.52%,the intra-RSD was 2.57%~5.76%,and inter-RSD was 2.27%~6.45%.Conclusion The SPE-HPLC method is simple to operate,high in recovery rate,high in accuracy and precision,good in stability and low in cost,meets the basic requirements of the guiding principles of clinical pharmacokinetic experiments,and the results are accurate and reliable.Chapter Two The study of the population pharmacokinetic model of the active metabolite of oxcarbazepine in Chinese epileptic patientsObjective To establish the population pharmacokinetic model of the active metabolite(10-monohydroxycarbamazepine,MHD)of oxcarbazepine(OXC)in Chinese epileptic patients and gain the pharmacokinetic parameters for optimizing individualized dosing regimens.Methods The plasma concentrations of MHD and corresponding clinical datas were collected from outpatient and hospitalized patients with epilepsy.A population pharmacokinetics(PPK)model was constructed using NLME software.After establishing basic pharmacokinetic model and statistical model,a number of covariates were screened for their influence on the pharmacokinetic parameters of MHD.Bootstrap was applied to the raw data as internal validation.Results 165 blood samples of 107 epileptic patients were collected.MHD pharmacokinetics obeyed a one-compartment model with first-order absorption and elimination.The population values of pharmacokinetic parameters estimated in the final model were as follows: CL/F= 3.67 L·h-1,Vd/F=34.29 L,and Ka was fixed as 0.5 h-1.Concomitant antiepileptic drugs influenced the clearance of MHD,and body weight had an influence on apparent volume of distribution.Conclusions A PPK model of MHD in Chinese epileptic patients was established in this study,and was used for OXC clinical individualization therapy in epileptic patients.