Abstract
Sodium oxybate (SXB) is the sodium salt of gamma hydroxybutyrate (GHB), a substrate for the monocarboxylate transporter (MCT) that may be inhibited by nonsteroidal anti-inflammatory drugs. This study evaluated potential drug–drug interactions of SXB and ibuprofen with regard to pharmacokinetics (PK), pharmacodynamics (PD), and safety. Healthy volunteers were randomized to SXB + ibuprofen placebo, SXB + ibuprofen, or SXB placebo + ibuprofen in a three-period, double-blind, crossover design with a 2-day washout between periods. Ibuprofen/placebo (4x200mg capsules) was given qid every 4 h on days 1 and 2, and 1 h before and 3 h after the first SXB dose on day 3; SXB/placebo was given as two 3 g doses 4 h apart on day 3. Blood and urine samples were taken at predefined times for noncompartmental PK analysis. PD testing, performed during each treatment period, included the Karolinska Sleepiness Scale (KSS), and a selection of automated tests from CDR System (www.bracketglobal.com) including the Simple Reaction Time, Digit Vigilance, Choice Reaction Time, Tracking, and Numeric Working Memory tasks. Safety was assessed at specified time points, and throughout the study. 21 subjects enrolled and completed the study (95% male; 57% white; mean age 34.4 ± 8.4 years). Although mean plasma SXB concentrations were approximately 5% lower with ibuprofen co-administration ( P < 0.05), the 90% CIs of the geometric LS means for SXB PK parameters with and without ibuprofen were within the 80–125% equivalence range. Urinary excretion of SXB increased ∼2-fold with ibuprofen (mean renal clearance = 874.2 mL/h for SXB + ibuprofen and 463.6 mL/h for SXB alone; P < 0.0001), and the percent mean ratio of the geometric LS means was 194% (90% CI 172%, 219%) exceeding the equivalence range. Cognitive function impairments and increased sleepiness were observed with SXB with and without ibuprofen, but no PD interactions were observed. The most common adverse events (AEs) were consistent with the drug profiles. AEs in ⩾2 subjects with SXB + ibuprofen were somnolence ( n = 15), euphoric mood ( n = 10), dizziness ( n = 5), headache ( n = 3), and nausea ( n = 2), and reflect a combined effect of both drugs. Although renal excretion of SXB increased, likely as a result of MCT inhibition by ibuprofen, plasma PK ratios were within the equivalence range, suggesting the interaction was not clinically significant. No PD interactions were observed, and AEs were consistent with the drug profiles. This study was sponsored by Jazz Pharmaceuticals, Inc.
Published Version
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