Population pharmacokinetics of lamotrigine co-administered with valproic acid in Chinese epileptic children using nonlinear mixed effects modeling.

Abstract

The aims of this study were to develop a population pharmacokinetic (PPK) model of lamotrigine (LTG) in Chinese epileptic children by using nonlinear mixed effects modeling (NONMEM) and to investigate the effects of valproic acid (VPA) and genetic polymorphisms of the major metabolizing enzymes (UGT1A4, UGT2B7) on the pharmacokinetics of LTG. A total of 182 epileptic children who were treated with LTG as monotherapy or as part of combination therapy were included in this study as the model group, and 61 patients were included as the validation group. The steady-state serum trough concentrations of LTG and VPA were determined using a high-performance liquid chromatography method and fluorescence polarization immunoassay, respectively. Patients were genotyped for three single nucleotide polymorphisms (UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 802C>T). PPK analysis was performed with NONMEM using first-order absorption and elimination. Bootstrap, normalized prediction distribution errors and external evaluations were performed to determine the stability and predictive performance of the model. For the final model, the oral clearance (CL/F) of LTG was estimated to be 0.705L/h with inter-individual variability (IIV) of 21.3%. The estimates generated by NONMEM indicated that the LTG CL/F was significantly influenced by patient body weight (increased with an exponent of 0.574) and VPA concentration (decreased with linearity of 0.273 with co-administration). However, no significant effects of UGT1A4 or UGT2B7 polymorphisms on LTG CL/F were noted in this population of Chinese children. This study confirms the interaction of LTG with VPA, which likely depends on VPA concentration. The LTG PPK model developed in this study could be useful for individualizing LTG dosage regimens in pediatric patients receiving combination therapy, especially therapy that includes VPA.