Evaluation of drug–drug interactions of sodium oxybate with divalproex: Results from a pharmacokinetic/pharmacodynamic study

Abstract

To evaluate drug-drug interactions of sodium oxybate (SXB) and divalproex sodium ER (DVP) with regard to PK, PD, and safety. SXB is the sodium salt of gamma-hydroxybutyrate (GHB), a substrate for monocarboxylate transporter and GHB dehydrogenase; both are inhibited by valproic acid. Healthy volunteers were randomized to one of 4 treatment sequences in a 5-period, double-blind, crossover design with washout between periods. During Periods 1 and 2, subjects received two 3g doses of SXB or placebo 4h apart in a crossover fashion (days 1 and 3). In Period 3 (days 5–14), subjects received DVP 1250mg, and continued DVP during Periods 4 and 5 (days 15–18), with two 3 g doses of SXB or placebo administered 4h apart in a crossover fashion on Days 15 and 18. Blood and urine samples were taken at predefined times for PK analysis. PD testing, performed during SXB treatment, included the Karolinska Sleepiness Scale, and several automated tests from CDR System (www.bracketglobal.com) including Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Tracking, and Numeric Working Memory tasks. Safety was assessed throughout the study. 20 subjects enrolled and completed the study (all male, 65% white, mean age 33.9 ± 6.6 y). Geometric LS means of SXB with SXB + DVP relative to SXB alone were significantly higher for plasma AUC0-inf (349.7 vs. 275.6 μg * h/mL; P < 0.0001) and renal clearance (606.0 vs. 480.5 mL/h; P < 0.001), and upper bounds of the 90% CIs of the percent mean ratios exceeded the equivalence range of 80–125%. No changes in DVP PK were observed with SXB+DVP. SXB induced sleepiness and cognitive impairments. SXB + DVP produced significantly greater deficits ( P < 0.05) at several time points than SXB alone in numeric working memory mean reaction time, simple reaction time mean, digit vigilance accuracy, choice reaction time accuracy, continuity of attention, and tracking distance from target. The most common adverse events (AEs) were consistent with the drug profiles. AEs in ⩾2 subjects with SXB + DVP were somnolence, n = 18; euphoric mood, n =10; dizziness, n = 7; and nausea, n = 4. SXB + DVP showed changes in SXB PK and renal clearance consistent with GHB dehydrogenase and monocarboxylate transporter inhibition. SXB produced sleepiness and cognitive impairments; some cognitive domains showed greater impairment with DVP co-administration, consistent with SXB PK changes. AEs with SXB + DVP reflect a combined drug effect. This study was sponsored by Jazz Pharmaceuticals, Inc.