The Study On The Evaluation And Application Of Population Pharmacokinetic Models Of The Active Metabolite Of Oxcarbazepine In Pediatrics With Epilepsy

Purpose:Based on the concentration data of the active metabolite monohydroxycarbazepine（MHD）of oxcarbazepine of pediatric patients with epilepsy,to evaluate the predictive precision and accuracy of population pharmacokinetic（Pop PK）models of MHD in pediatric patients with epilepsy.By quantitatively analyzing the effect of influential factors on the estimation of pharmacokinetic parameters of MHD in pediatric patients with epilepsy,to establish a concentration-dose predictive model for individualized treatment.Methods:1.External validation of the population pharmacokinetic models of the active metabolite of oxcarbazepine in pediatric patients with epilepsy.Databases including CNKI,Wanfang,EMBASE and Pub Med were searched for Pop PK studies based on a nonlinear mixed effect modelling approach of MHD.Predominant parameters of Pop PK models were extracted and imported into NONMEM software.The concentration data of MHD blood samples from children with epilepsy were fitted with identified Pop PK models.Their fitting efficiency was tested by model evaluation methods including goodness-of-fit,Bootstrap,check of predictive errors and normalized prediction distribution errors.2.The establishment and application of the population pharmacokinetic model of the active metabolite of oxcarbazepine in pediatric patients with epilepsy.Based on nonlinear mixed effect modeling approach,concentration data of 299 blood samples from 449 pediatric patients with epilepsy were retrospectively collected for model establishment and evaluation,respectively.The final model was evaluated by internal and external validation methods.The steady-state trough concentration(C_ss)was predicted based on the final model and its probability of target attainment was calculated.Then the final model was imported into JPKD software for constructing predictive model of individual dose-concentration.The predictive model was validated by 159 blood samples of 100 patients.Results:1.External validation of the population pharmacokinetic models of the active metabolite of oxcarbazepine in pediatric patients with epilepsy.8 Pop PK models and 159 blood samples from 100 pediatric patients with epilepsy were included into analysis.All published models showed an insufficient fitting efficiency,except model A and H which fit relatively better with observed value than other models.The evaluation results recall inadequate predictive accuracy of published Pop PK models of MHD in pediatric patients(MAPE>30%,F₃₀<50%).2.The establishment and application of the population pharmacokinetic model of the active metabolite of oxcarbazepine in pediatric patients with epilepsy.The final model is:CL/F（L/h）=2.47·EXP（0.214）·（WT/40）^0.381·（TAMT/900）^0.324.The typical value of apparent clearance rate is 2.47 L/h,and its coefficient value is 21.7%.For most pediatric patients weighing 10～70 kg,after given a twice daily dosing regimen of 20 mg·kg^-1·d^-1,the probability of C_ssachieving safe therapeutic range could be more than 93%,which indicates that this regimen could be used as maintenance dose for pediatric patients with epilepsy.The individual predicted value fits linearly with the observed value.The relative error of 93%blood samples was less than±20%.Conclusion:All published Pop PK models poorly fit with the concentration data of pediatric patients with epilepsy.Body weight and total daily dose were identified as significant covariates for clearance of MHD,which could be further used for estimating the pharmacokinetic parameters of MHD for pediatric patients.For most pediatric patients with epilepsy,a maintenance dose of 20 mg·kg^-1·d^-1 is enough for achieving effective steady-state trough concentration.The established dose-concentration prediction model in this study shows good predictability and stability,which could be utilized for individualized treatment in clinical practice.