Daniela Milosheska1, Bogdan Lorber2, Tomaž Vovk1, Matej Kastelic3, Vita Dolžan3, Iztok Grabnar1. 1. Faculty of Pharmacy, University of Ljubljana, 1000, Ljubljana. 2. Department of Neurology, University Medical Centre Ljubljana, 1000, Ljubljana. 3. Faculty of Medicine, Institute of Biochemistry, University of Ljubljana, 1000, Ljubljana, Slovenia.
Abstract
AIMS: This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS: We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTS: With a base model absorption rate (interindividual variability) was estimated at 1.96 h(-1) (72.8%), oral clearance at 2.32 l h(-1) (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONS: Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings.
AIMS: This study aimed to develop a population pharmacokinetic model for quantitative evaluation of the influence of genetic variants in metabolic enzymes and transporters on lamotrigine pharmacokinetics while taking into account the influence of various clinical, biochemical and demographic factors. METHODS: We included 100 patients with epilepsy on stable dosing with lamotrigine as mono or adjunctive therapy. Lamotrigine and lamotrigine N-2-glucuronide concentrations were determined in up to two plasma samples per patient. Patients were genotyped for UGT1A4, UGT2B7, ABCB1 and SLC22A1. Population pharmacokinetic analysis was performed by non-linear mixed effects modelling. Prior knowledge from previous pharmacokinetic studies was incorporated to stabilize the modelling process. A parent-metabolite model was developed to get a more detailed view on the covariate effects on lamotrigine metabolism. RESULTS: With a base model absorption rate (interindividual variability) was estimated at 1.96 h(-1) (72.8%), oral clearance at 2.32 l h(-1) (41.4%) and distribution volume at 77.6 l (30.2%). Lamotrigine clearance was associated with genetic factors, patient's weight, renal function, smoking and co-treatment with enzyme inducing or inhibiting drugs. In patients with UGT2B7-161TT genotype clearance was lower compared with GT and GG genotypes. Clearance was particularly high in patients with UGT2B7 372 GG genotype (compared with AA genotype it was 117%; 95% CI 44.8, 247% higher). CONCLUSIONS: Variability in lamotrigine pharmacokinetics is large and quantification of its sources may lead to more precise individual treatment. Genotyping for UGT2B7 may be useful in various clinical settings.
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Authors: Sven C van Dijkman; Nico C B de Jager; Willem M Rauwé; Meindert Danhof; Oscar Della Pasqua Journal: Clin Pharmacokinet Date: 2018-11 Impact factor: 6.447
Authors: Sven C van Dijkman; Nico C B de Jager; Willem M Rauwé; Meindert Danhof; Oscar Della Pasqua Journal: Clin Pharmacokinet Date: 2018-08 Impact factor: 6.447