Z Hussein1, J Posner. 1. Department of Clinical Pharmacology, GlaxoWellcome Research and Development, UK.
Abstract
AIMS: To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks. METHODS: The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41-107 kg, respectively. A one-compartment compartment model with first-order absorption and elimination was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modelling (NONMEM), with first-order estimation. Oral clearance (CLo), apparent volume of distribution (V/F) and absorption rate constant (Ka) were the main pharmacokinetic parameters. RESULTS: CLo was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto-induction CLo increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h(-1), and was 28.7% lower in Asians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V/F was examined and none was statistically significant. The final population estimate of V/F was 77.4 l with an interpatient variability of 34%. CONCLUSIONS: In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.
RCT Entities:
AIMS: To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks. METHODS: The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41-107 kg, respectively. A one-compartment compartment model with first-order absorption and elimination was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modelling (NONMEM), with first-order estimation. Oral clearance (CLo), apparent volume of distribution (V/F) and absorption rate constant (Ka) were the main pharmacokinetic parameters. RESULTS:CLo was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto-induction CLo increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h(-1), and was 28.7% lower in Asians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V/F was examined and none was statistically significant. The final population estimate of V/F was 77.4 l with an interpatient variability of 34%. CONCLUSIONS: In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.
Authors: Surulivelrajan Mallaysamy; Martin G Johnson; Padma G M Rao; Thiyagu Rajakannan; Lokesh Bathala; Karthik Arumugam; Johan G C van Hasselt; Devarakonda Ramakrishna Journal: Eur J Clin Pharmacol Date: 2012-06-02 Impact factor: 2.953