Population Pharmacokinetics of Lamotrigine Adjunctive Therapy in Adults with Epilepsy

Abstract

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…The induction effect of PB or CBZ was observed; thus, CL was increased by 1.9-2.4 fold compared to monotherapy. These results are similar to those from previous studies conducted in patients taking these drugs that also reported increased LTG CL with values ranging from 0.044 to 0.084 L·h -1 ·kg -1 [7,[25][26][27] .…”

“…This unexplained variability was of similar magnitude to those reported in earlier studies [7,[13][14][15][16][32][33][34] .…”

“…Despite LTG's wide clinical use, standard npg dosage regimens continue to be used even though they may often be suboptimal because of the high variability found in CL values in the target population [7,10,[13][14][15][16][17][18] . This observation, together with previous studies that have established definable relationships between LTG blood concentrations and therapeutic and toxic effects [19][20][21] , justify TDM as an indicator of drug exposure for the individualization of LTG doses [4][5] .…”

“…The traditional method for calculating individual PK parameters was to collect multiple (up to [7][8][9][10] blood samples from a single patient at different times after a single dose. This method was not always accepted by patients, especially children.…”

“…A one-compartment, open kinetic model with first-order absorption and elimination (specified to NONMEM by the ADVAN2 and TRANS2 routines) was assumed according to the available bibliographic information [7][8][9][10] . Because the LTG steady-state trough plasma concentration data collected did not provide information about the extent and rate of absorption processes, the bioavailability (F) and absorption rate (K a ) were fixed at 1.0 and 1.0 h -1 , respectively [7] . Thus, the PK parameters estimated were CL (the most important PK parameter in terms of optimizing drug dosage regimens) and V d .…”