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

Abstract

To evaluate drug–drug interactions between sodium oxybate (SXB) and diclofenac with regard to pharmacokinetics (PK), pharmacodynamics (PD), and safety. SXB is the sodium salt of gamma hydroxybutyrate (GHB), a substrate for the monocarboxylate transporter that may be inhibited by diclofenac, which also binds to GHB receptors in the brain. Healthy volunteers were randomized to SXB + diclofenac placebo, SXB + diclofenac, or SXB placebo + diclofenac in a 3-period, double-blind, crossover design with a 2-day washout between periods. Diclofenac/placebo (50 mg immediate-release) was given qid every 4 h days 1 and 2, and 1 h before and 3 h after the first SXB dose day 3; SXB/placebo was given as two 3 g doses 4 h apart day 3. Blood and urine were sampled at predefined times for noncompartmental PK analysis. PD testing at the end of each treatment period included the Karolinska Sleepiness Scale (KSS), 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 at specified time points, and throughout the study. Of 22 subjects (77% male, 55% white, mean age 34.2±6.6 y), 20 completed the study. SXB PK were similar with and without diclofenac. Geometric LS mean percent ratios for SXB PK parameters with and without diclofenac were 106.7% for Cmax, 100.5% for AUC0-inf, and 94.8% for renal clearance; all 90% CIs were within the 80%-125% equivalence range, suggesting no PK drug-drug interaction. A similar lack of differences was observed for diclofenac PK. SXB induced sleepiness and attentional impairments. SXB + diclofenac had significantly less impairment at several time points compared with SXB alone on accuracy and speed on digit vigilance, choice reaction time, and power of attention (P<0.05). SXB effects on KSS and tracking performance were not reduced by diclofenac. The most common adverse events (AEs) were consistent with the drug profiles. AEs in &#8805;2 subjects with SXB + diclofenac (somnolence, n = 11; dizziness, n = 6; euphoric mood, n = 5; nausea, n = 5; headache, n = 4; vomiting, n = 3; dry mouth, n = 2; and feeling hot, n = 2) reflect a combined effect of both drugs. Co-administration of SXB and diclofenac did not significantly change the PK of either drug. Diclofenac co-administration appeared to reduce SXB-associated impairments to attention and information processing relative to SXB alone. AEs with SXB + diclofenac reflect combined drug effects. This study was sponsored by Jazz Pharmaceuticals, Inc.