Validation of population pharmacokinetic parameters of phenytoin using theparallel Michaelis-Menten and first-order elimination model

This study was conducted to assess whether the parallel Michaelis-Menten an d first-order elimination (MM+FO) model fitted the data better than the Mio haelis-Menten (MM) model, and to validate the MM+FO model and its parameter estimates. The models were fitted to 853 steady state dose : serum concent ration pairs obtained in 332 adults with epilepsy using nonlinear mixed-eff ects modeling (NONMEM). The MM+FO model fitted the data better than the MM model. The validity of the pharmacokinetic models and the estimated populat ion parameter values was tested using the naive prediction method. The esti mation and validation of the pharmacokinetic parameters were undertaken in two separate patient groups (cross-validation) obtained by splitting the da ta set. Patients were randomly allocated to two equally matched groups (gro ups 1 and 2). The predictive performance was assessed using 770 paired pred icted versus actual dose or measured serum concentrations. The population p harmacokinetic parameters estimated by NONMEM in group 1 were validated in group 2 and vice versa. When predicting steady state set-um concentration, the MM+FO model was clearly superior to the MM model (mean bias of 0.91 and 8.13 mg/L, respectively).