Total and unbound dolutegravir plasma concentrations were measured in HIV-infected individuals on once-daily 50 mg dolutegravir-containing combination ART prior to and after the concomitant administration of valproic acid (30 mg/kg/day orally divided into two equal doses). Data from 6 participants receiving valproic acid showed that during valproic acid administration, total dolutegravir levels decreased sharply from 1.36 mg/L on day 0 to 0.85 mg/L, 0.31 and 0.14 mg/L on days 1, 7 and 14. Total dolutegravir concentrations in the 4 control participants not receiving valproic acid remained comparable during the same period: 1.27 ± 1.49 mg/L. A parallel increase was observed in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. This study supports that the decrease in total dolutegravir concentrations in presence of valproic acid is mainly due to protein binding displacement of dolutegravir by valproic acid. If dolutegravir is taken with food, this interaction is probably not clinically relevant.

Following the unexpected drug-drug interaction between dolutegravir and valproic acid, plasma concentrations of several antiretrovirals drugs were analyzed when administered in presence and absence of valproic acid. Drug concentrations were obtained from the TDM registry of the University Hospital of Torino. A total of 134 individuals receiving concomitantly valproic acid and antiretroviral drugs were identified. With the exception of dolutegravir, no significant decrease in plasma exposure was observed for the other antiretrovirals. Median (IQR) dolutegravir Ctrough was 132 ng/mL (62-227) in presence of valproic acid vs 760 ng/mL (333-1407) in absence of valproic acid (n=29). Raltegravir Ctrough was 337 ng/ml (99-632) vs 231 ng/mL (87-566) (P =0.873, n=27). This study showed no major effect of valproic acid on antiretroviral total concentrations with the exception of dolutegravir.

A retrospective analysis of dolutegravir trough concentrations in 363 samples (from 149 patients) showed lower trough concentrations in 11 samples from 7 patients on valproic acid (0.068 µg/ml vs 0.557 µg/ml). Detailed pharmacokinetic sampling was performed in two hospitalized patients requiring valproic acid while on dolutegravir-based regimens. When compared to a mean reference AUC value of 75.1 µg.h/mL for dolutegravir twice daily, dolutegravir AUC in the first patient was 82% lower with IV valproic acid and 87-91% lower with oral valproic acid. In the second patient, dolutegravir AUC was 80% lower with oral valproic acid when compared to the mean reference AUC.