Evidence of Sex-Related Pharmacodynamic Differences in Photosensitive Epilepsy Treated with Valproate: Findings from a Retrospective, Observational, Single-Center, Within-Patient, Cohort Study.

Background And Objective: Sexual dimorphism in drug efficacy, beyond pharmacokinetics (PK), remains underexplored. Significant sex differences exist in drug metabolism and adverse events, highlighting the need for personalized medicine. The objective of our study was to assess whether there are sex differences in the pharmacodynamic (PD) response to valproic acid (VPA) in photosensitive epilepsy, focusing on electroencephalographic (EEG) biomarkers (e.g., photoparoxysmal response [PPR] raw data and transformed PPR data, the standardized photosensitivity range [SPR]) that cannot be attributed to pharmacokinetics alone. On the basis of some exploratory published evidence plus our own clinical observations of VPA treatment in patients with epilepsy plus photosensitivity over time, we hypothesized that an EEG pharmacodynamic difference might exist between females and males.

Methods: We conducted a retrospective, observational, single-center, within-patient EEG cohort study conducted on antiseizure medicine (ASM)-naïve photosensitive individuals before and after VPA treatment (nonrandomized). The data we reviewed had been collected from a referral hospital in the Netherlands from 1990 to 2000. Changes in EEG data, including raw PPR data (transformed into SPR), were analyzed before and after VPA therapy in 48 patients, including 27 females and 21 males, ranging in age from 8 to 50 years old for the entire cohort. Co-primary outcomes included a between-sex comparison in the distribution of within-patient SPR changes from pre-VPA to steady-state VPA therapy, and complete PPR elimination on EEG. Secondary outcomes included the comparison of percentage of males and females meaningfully responding to VPA across SPR change categories, VPA dose, potential impact of plasma [VPA] concentrations on SPR changes, and associaton of patient age with SPR values. Statistical analyses included univariate linear regression models, chi-squared tests, non-parametric Wilcoxon-Mann-Whitney tests, and Fisher's exact tests.

Results: Our first co-primary outcome revealed a statistically significant difference in the distribution of within-patient SPR changes from pre-VPA to steady-state VPA therapy. Males experienced a significantly greater reduction in SPR compared with females. The mean decrease in SPR was -7.0 ± 2.6 in males only versus -3.9 ± 3.3 in females only (p = 0.0018). The next co-primary outcome, the percent of patients with complete PPR elimination, or a SPR value = 0 on second EEG, was observed in ten (47.6%) males compared with four (14.8%) females, a 3.2-fold difference (p = 0.0237). One secondary outcome, the percentage of males with a VPA clinically meaningful to optimal response was 1.93-fold greater than females, at 100:51.8%, respectively (p < 0.0001). Between-sex VPA total daily milligram dose did not differ. Plasma [VPA] concentrations, although nearly twice as high in females, were not statistically different between sexes and [VPA] did not correlate with SPR changes in females.

Conclusions: In our mixed-age population of pediatric, adolescent, and younger adults, significant sex differences were observed in the response of the PD EEG biomarkers, the PPR and SPR, to VPA for both primary outcomes. Males showed both a statistically greater reduction in EEG SPR and a statistically higher percent elimination of PPR on EEG with chronic VPA treatment compared with females. The percent of males having a clinically meaningful EEG SPR response to VPA, a secondary outcome, was almost two-fold greater for males compared with females. These findings emphasize the importance of considering sex in treatment planning and suggest that inherent biological differences may influence drug efficacy, advocating for further research to enhance personalized medical strategies.