Prediction of lacosamide concentrations to support dose optimization during pregnancy

• Published in: Epilepsia (Copenhagen) 2024-12
• Main Authors: Barry, Jessica M, Illamola, Sílvia M, Pennell, Page B, Sherwin, Catherine M, Meador, Kimford J, Birnbaum, Angela K
• Format: Article
• Language: English
• ISSN: 1528-1167; 1528-1167
• DOI: 10.1111/epi.18184

We aimed to quantify and predict lacosamide exposure during pregnancy by developing a pregnancy physiologically-based pharmacokinetic model, allowing the prediction of potential dose increases to support maintaining a patient's preconception lacosamide concentrations. Models for nonpregnant adults and pregnant female patients were constructed using physiochemical and pharmacological parameters identified from literature review. Evaluation of plasma concentration data from human males was digitized from the literature. Concentration data in nonpregnant and pregnant human females were available from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a longitudinal observational study which followed 11 nonpregnant and 16 pregnant women receiving lacosamide. Evaluation was conducted qualitatively with visual overlay (>80% of observed concentrations within 90% confidence interval) and quantitatively with average fold error and absolute average fold error (0.8-1.25 ratio acceptance criteria). Simulations of intensively-sampled dosing regimens at steady-state dosing across multiple gestational ages were conducted in Simcyp to evaluate the potential changes in lacosamide pharmacokinetics during pregnancy. Additional simulations were performed to explore the effects of cytochrome polymorphisms and glomerular filtration rate variability. The model adequately described the evaluation data in nonpregnant adults and pregnant adults between 10 and 40 weeks of gestation. Estimates in patients at 40- weeks of gestation indicated that lacosamide clearance increased by 48.2% compared to nonpregnant patients. Maximum lacosamide concentration (Cmax) during a simulated dosing interval also fell by 30% from preconception to 40 weeks. A simulated dose increase of 50 mg once daily at 10 weeks of gestation supported maintenance of preconception concentration for a typical patient taking the most common dosing regimen of 200 mg, twice daily (BID), preconception. Simulated changes in lacosamide concentration align with the limited data available in observational studies. Our simulations support the use of therapeutic drug monitoring and dose adjustments to maintain the efficacy of lacosamide pharmacotherapy.