Gestational Changes in Antiseizure Medication Concentrations and the Impact of Polytherapy: A Prospective Multicenter...

Pregnancy alters the pharmacokinetics of antiseizure medications (ASMs). The aim of this study was to quantify gestational changes in ASM concentrations and identify independent covariates among women with epilepsy in China.

In this prospective, multicenter observational cohort study in China, women with epilepsy aged 18-45 years were enrolled and followed longitudinally. Steady-state trough ASM concentrations were measured, with concentration-to-dose (C/D) ratio as the primary pharmacokinetic parameter. Linear mixed-effects models with model averaging were used to evaluate the independent effects of gestational age, concomitant ASMs, and demographic covariates on ASM C/D ratios.

A total of 947 women were included and contributed 1,638 samples between 2019 and 2025, including 1,187 samples collected during nonpregnant periods (821 women, mean age 29.31 ± 8.38 years) and 451 during pregnancy (228 women, mean age 28.67 ± 4.30 years), with 64.3% receiving polytherapy. Lamotrigine exhibited the greatest gestational effect, with C/D ratios declining by 28.8% (β = -0.339; 95% CI -0.508 to -0.339; p < 0.001), 54.3% (β = -0.784; 95% CI -0.938 to -0.629; p < 0.001), and 63.2% (β = -1.001; 95% CI -1.192 to -0.809; p < 0.001) in the first, second, and third trimesters, respectively, reaching a nadir of -65.8% at 32 weeks. Levetiracetam declined by 26.2% (β = -0.303; 95% CI -0.446 to -0.160; p < 0.001), 40.1% (β = -0.512; 95% CI -0.645 to -0.379; p < 0.001), and 31.0% (β = -0.371; 95% CI -0.525 to -0.217; p < 0.001), reaching a nadir of -35.5% at 24 weeks. The metabolite of oxcarbazepine declined by 23.1% (β = -0.262; 95% CI -0.373 to -0.152; p < 0.001), 32.6% (β = -0.394; 95% CI -0.489 to -0.299; p < 0.001), and 44.3% (β = -0.585; 95% CI -0.695 to -0.475; p < 0.001). Lacosamide significantly decreased in the second trimester (-10.8%; β = -0.207; 95% CI -0.399 to -0.014; p = 0.035). Perampanel showed an increasing trend but was limited by sample and polytherapy. Concomitant ASMs primarily shifted baseline C/D ratios without altering gestational changes, and several drug-drug interactions were identified. Higher body weight was associated with lower C/D ratios for most ASMs, except for perampanel. Interindividual variability remained the dominant factor determining C/D ratios over measured covariates.

Pregnancy was the primary driver of declining C/D ratios, and concomitant ASMs and body weight acted as secondary modifiers. These findings support individual therapeutic drug monitoring.

ChiCTR2100046318 (Chinese Clinical Trial Registry, chictr.org.cn).