Population pharmacokinetics of lamotrigine in Indian epileptic patients.

Mallaysamy, Surulivelrajan; Johnson, Martin G; Rao, Padma G M; Rajakannan, Thiyagu; Bathala, Lokesh; Arumugam, Karthik; van Hasselt, Johan G C; Ramakrishna, Devarakonda

PURPOSE The aim of this analysis was to describe the pharmacokinetics of oral lamotrigine (LTG) in Indian epileptic patients using a population pharmacokinetic (PPK) modeling approach to confirm that the PK is similar to that of the Caucasian population, and to evaluate and confirm the impact of covariates predictive of inter-individual variability using a simulation platform. METHODS Blood samples were obtained from 95 patients, and LTG plasma concentrations were determined. Population PK modeling was performed using NONMEM. A one-compartment PK model with first-order absorption and elimination was used to describe the LTG PK. Log-likelihood profiling and normalized prediction distribution errors (NPDE) were used for model evaluation. A simulation study was performed to investigate dose regimens. RESULTS Clearance (CL) was estimated to be 2.27 L/h with inter-individual variability (IIV) of 29 CV%. Volume of distribution (V) was estimated to be 53.6 L (31 CV% IIV). Body weight and concurrent use of carbamazepine and valproate were identified as significant covariates on clearance. Log-likelihood profiling indicated that parameters could be estimated with adequate precision, and NPDE indicated that the model adequately described the data observed. The simulation study illustrated the impact of carbamazepine and valproate on LTG PK, and negligible differences in PK between Indian and Caucasian patients. CONCLUSIONS This is the first PK analysis of LTG in Indian patients. The population PK model developed adequately described the data observed. Comparison of identified PK parameters with previous PK analyses in Caucasian patients indicates that CL of LTG is similar, while V is somewhat lower compared with Caucasian patients, but this is not expected to lead to relevant differences in PK profiles during steady state.