Application of PBPK model to predict the effect of pregnancy and CYP polymorphism on systemic exposure of phenytoin

Purpose: To simulate the effect of pregnancy and genetic polymorphism on the steady state plasma concentration-time profile of phenytoin using PBPK modeling in SimcypRTM. Phenytoin is an antiepileptic medication with a narrow therapeutic range. Its metabolism is primarily mediated by CYP2C9 and CYP2C19. Physiological changes associated with pregnancy and CYP polymorphisms could result in altered phenytoin levels, resulting in toxicity in patients.;Methods: PBPK modeling was performed using the SimcypRTM Simulator (V.15). The model was first verified by comparing predicted phenytoin levels following both single and multiple dosing against published data from heathy volunteers (1.2). The verification metric was fold-error (FE, ratio of predicted vs observed value) in Cmax and AUC. The model was then used to predict the changes in total and unbound phenytoin concentration at steady state (Css) in all three trimesters of pregnancy as well as post-partum. In second part of study, differences in steady state phenytoin levels among Japanese and Chinese polymorphic patient populations were predicted, and the results were correlated with CYP2C metabolizer status (wild-type vs. poor metabolizers) (3.4). The predictive performance of the model was evaluated against observed clinical data (average steady state concentrations). Additionally, systemic exposure of phenytoin was compared in patients with various CYP2C9 genetic polymorphisms based on published Km and Vmax values for different genotypes (5).;Results: 46.92% and 35.61% decrease in total and unbound phenytoin concentration had been predicted from first (Ti) to third (T3) trimester respectively. Predicted results were verified by comparing it against published clinical data and fold error range of 0.89-1.19 had been observed. 78.81% and 63.04% increase in steady state concentration of phenytoin had been predicted when CYP2C poor metabolizer had been compared against CYP2C wild-type in Chinese and Japanese population respectively. Predicted results where verified by comparing it with observed clinical data and fold error ranged from 0.91-1.96.;Conclusion: Pregnancy and CYP2C polymorphism is associated with altered systemic exposure of phenytoin. a medication with a narrow therapeutic range. PBPK modeling with the SimcypRTM Simulator was able to capture changes in steady state phenytoin plasma concentrations in pregnant population as well as patients who are poor metabolizers of CYP2C9 and/or CYP2C19, and offers a practical approach to guide dosing adjustments of CYP substrates based on patient genotype.