# Placental transfer of third-generation antiepileptic drugs: in vivo lacosamide case study and in vitro investigation of transporter inhibition by lacosamide and perampanel

## TL;DR

This study examines how two newer epilepsy drugs, lacosamide and perampanel, pass through the placenta and affect transporter proteins during pregnancy.

## Contribution

The study provides new in vivo and in vitro data on placental transfer and transporter inhibition by third-generation antiepileptic drugs.

## Key findings

- Lacosamide reached fetal plasma at concentrations near the lower end of the maternal therapeutic range.
- High lacosamide doses inhibited BCRP function in vitro, but perampanel did not affect major efflux transporters.
- Fetal-to-maternal plasma concentration ratios for lacosamide likely remained below 1.0.

## Abstract

Antiepileptic drugs must be continually used to control seizures in pregnant people with epilepsy. Lacosamide (LCM) and perampanel (PER) are third-generation antiepileptic drugs that were introduced to clinical practice in 2008 and 2012, respectively. LCM and PER are increasingly being prescribed. However, little information is available regarding the safety or placental transfer of LCM and PER during pregnancy. We investigated the placental permeability of LCM in vivo and the effects of LCM and PER on efflux transporters in human placental cells in vitro.

Clinical umbilical cord and maternal plasma samples were collected from a woman who had been receiving a regular oral regimen of 100 mg LCM twice daily. The LCM concentrations in the samples were quantified using ultra-high-performance liquid chromatography/tandem mass spectrometry. Accumulation assays were conducted using in vitro syncytiotrophoblast models to determine the effects of LCM and PER on the functions of efflux transporters, including breast cancer resistance protein (BCRP/ABCG2), multidrug resistance proteins (MRPs/ABCCs), and P-glycoprotein (P-gp/ABCB1).

The LCM concentrations in the maternal plasma and umbilical cord plasma samples were 4.02 µg/mL (predelivery trough level) and 3.22 µg/mL (3.5 h after last dose), respectively. The LCM concentration in the umbilical cord plasma was near the lower end of the maternal therapeutic range, and the fetal-to-maternal plasma concentration ratio likely remained below 1.0. Therapeutic concentrations of LCM and PER did not increase the accumulation of fluorescent substrates of the efflux transporters in the in vitro assays. In contrast, high LCM doses increased the accumulation of BODIPY™ FL prazosin, a BCRP substrate, whereas PER did not affect the accumulation of any substrate.

LCM was transferred to the fetus at concentrations close to the lower end of the therapeutic range, suggesting that fetal plasma levels did not exceed the maternal levels. High LCM concentrations inhibited BCRP function in vitro, whereas PER did not inhibit major placental efflux transporters.