(T1530-02-11) Prediction of Lacosamide Concentrations to Optimize Dosing during Pregnancy

Purpose: Lacosamide concentrations may decline during pregnancy, resulting in the need for changes in dose to avoid seizures. Predicting the degree of dose change is critical to maintaining a patient’s lacosamide preconception concentrations. Using a pregnancy physiologically-based pharmacokinetic (PBPK) model, our objective was to identify the extent and timing of dose changes.

Methods: Physiochemical and pharmacokinetic parameters were identified in the literature to develop nonpregnant and pregnant models in Simcyp (v22, Certara Inc.). Concentration data in male patients was digitized from the literature to support model evaluation. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study provided observational longitudinal plasma concentration data in 11 nonpregnant control and 16 pregnant human females receiving lacosamide at multiple time points (3 during pregnancy, at birth, and 3 postpartum).¹ The model was considered acceptable if >80% of observed concentrations were visually contained within the 90% confidence interval. Average fold error and absolute average fold error criteria (0.8-1.25) were used to assess accuracy and precision. Intensively-sampled profiles were simulated at various steady-state dosing regimens across multiple gestational ages to predict lacosamide concentrations and changes in lacosamide pharmacokinetics during pregnancy. Other simulations were conducted to explore the effects of cytochrome polymorphisms and glomerular filtration rate.

Results: Acceptance criteria were met for the nonpregnant model. The pregnant model between 10-40 weeks also met all acceptance criteria. During pregnancy, the model predicted a typical patient will experience a 48.2% increase in clearance compared to the nonpregnant baseline at 40-weeks compared. The maximum lacosamide concentration (Cmax) decreased by 30% during the duration of pregnancy. For a typical patient receiving 200 mg BID of lacosamide prior to pregnancy, a 50 mg once-daily dose increase (i.e., 450 mg daily dose, 200 mg am/250 mg pm) at 10-weeks gestational age supported continued maintenance of preconception concentration.

Conclusion: Lacosamide concentrations predicted by the PBPK models were supported by the available data. Estimated lacosamide pharmacokinetic changes during pregnancy captured trends seen in observed studies. This study emphasizes the need for regular concentration monitoring and possible dosage changes to properly control lacosamide treatment during pregnancy, therefore ensuring both maternal health and fetal safety.

References: 1. Pennell PB, Karanam A, Meador KJ, et al. Antiseizure Medication Concentrations During Pregnancy: Results From the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) Study. JAMA Neurol. 2022;79(4):370-379. doi:10.1001/jamaneurol.2021.5487

Acknowledgements: This work was partially funded by NIH/NICHD grant R01HD105305, NIH/NINDS/NICHD U01-NS038455, and
the University of Minnesota CTSI UL1TR002494. Dr. Pennell has received honoraria and travel reimbursement for CME lectures at AES, AAN, and various medical schools, and royalties from UpToDate, Inc as a contributing author.