Empiric dosing strategies to predict lamotrigine concentrations during pregnancy

AbstractIntroductionMaintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy.ObjectiveOur objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity.MethodsLamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population level simulations (N=48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively.ResultsIndividual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8  weeks in the high clearance subpopulation depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7 to 100% of women in the high clearance chang...
Source: Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy - Category: Drugs & Pharmacology Authors: Tags: RESEARCH ARTICLE Source Type: research