The impact of menstrual cycle on the pharmacokinetics of antiseizure medications and lithium: a systematic review and meta-analysis

Introduction: Our aim was to quantify the impact of menstrual cycle phases on the pharmacokinetics of antiseizure medications (ASM) and lithium. Methods: A systematic literature search was conducted in PubMed/EMBASE in March 2024 for studies comparing levels of ASM and/or lithium in the early follicular and luteal phase. Concentration ratios between the follicular and the luteal phase were calculated. We performed a random-effects meta-analysis calculating between-timepoint differences in plasma concentration mean differences (MDs) and 95% confidence intervals (95% CIs). Subgroup analyses included cohorts stratified by the occurrence of catamenial exacerbation. Study quality was assessed using the ClinPK guidelines. Results: Fifteen studies investigating six ASM and lithium in 224 subjects were included. The highest concentration ratio was reported for carbamazepine (1.27, range 0.89–2.13) with an MD of 0.57 μg/mL, 95% CI: 0.41 to 0.72. Phenytoin concentration fluctuations were larger in subjects with (MD −3.51 μg/mL, 95% CI = −4.97 to −2.06) vs. without catamenial exacerbations (MD −1.18 μg/mL, 95% CI = −2.51 to 0.14, p = 0.02). Study quality was acceptable with an average rating score of 13.1. Conclusions: Data do not suggest major changes in ASM pharmacokinetics across the menstrual cycle. Participants with vs. without catamenial exacerbation had larger phenytoin concentration decreases in the early follicular compared to the luteal phase. Protocol registration: www.crd.york.ac.uk/prospero identifier is CRD42024527321.