Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy

Abstract

Purpose: to describe the population pharmacokinetics of lamotrigine (LTG) in developmentally disabled (DD) patients with epilepsy and (2) to determine if there is an effect of valproate (VPA) concentration on the extent of the pharmacokinetic interaction between VPA and LTG. Method: a NONMEM population analysis of steady-state LTG serum concentrations was conducted in patients receiving LTG either as mono or polytherapy with either an enzyme inducer (IND)-carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) or an inhibitor (VPA). Results: sixty-two patients (33.6±11.3 years, 47±9.9 kg) receiving LTG monotherapy ( n=19) or polytherapy with VPA ( n=15), inducer(s) ( n=32) or both ( n=5) were evaluated. LTG dose of 369±236 mg per day (8.1±5.9 mg/kg per day) achieved LTG plasma concentrations of 6.8±3.3 μg/ml. The observed LTG monotherapy, LTG+IND, and LTG+VPA oral clearance (Cl/ F) were 0.69±0.2, 1.60±0.65 and 0.2±0.05 ml/kg per min, respectively. The final LTG Cl/F model was dependent on body weight, concomitant VPA, and either single or multiple inducers. Including the serum concentrations of CBZ, PHT, or VPA in the model, did not significantly improve estimates of Cl/ F. Conclusion: LTG Cl/ F in DD patients is similar to literature values for ambulatory adult patients; however, low weight adult patients have higher elimination rates, as well as an increased response to enzyme induction. VPA inhibition of LTG Cl/F is maximal within the usually accepted therapeutic range for VPA.