Pharmacokinetics, bioavailability, and bioequivalence of lower-sodium oxybate in healthy participants in two open-label, randomized, crossover studies

American Academy of Sleep Medicine practice parameters designate sodium oxybate (SXB) as a standard of care for cataplexy, excessive daytime sleepiness (EDS), and disrupted night-time sleep in narcolepsy. Recently, a lower-sodium oxybate (LXB) with 92% less sodium than SXB was approved in the United States for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. Two phase I, open-label, randomized, single-dose crossover pharmacokinetic studies in healthy adults were conducted. Single 4.5-g oral doses of LXB and SXB were administered in a fasted or fed state. In the fasted state at equivalent oxybate doses, LXB, compared with SXB, had a lower maximum plasma concentration (C-max; study 1 [total aqueous volume, 240 ml]: 101.8 vs. 135.7 mu g/ml; study 2 [60 ml]: 94.6 vs. 123.0 mu g/ml), delayed time to C-max (T-max; study 1: 0.75 vs. 0.5 h; study 2: 1.0 vs. 0.5 h), but similar area under the curve (AUC; study 1: AUC(0-t), 235.4 vs. 263.9 mu g center dot h/ml; AUC(0-infinity), 236.5 vs. 265.2 mu g center dot h/ml; study 2: AUC(0-t), 241.5 vs. 254.7 mu g center dot h/ml; AUC(0-infinity), 243.1 vs. 256.3 mu g center dot h/ml). Bioequivalence criteria were met for AUC but not C-max (both studies). C-max and AUC were lower under fed than fasted conditions (LXB and SXB); differences between fed versus fasted were smaller for LXB than SXB. These pharmacokinetic differences between LXB and SXB are likely due to the lower sodium content in LXB. Pooled analyses demonstrated that a higher C-max is associated with a higher incidence of nausea and vomiting. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Sodium oxybate (SXB) and lower-sodium oxybate (LXB) are approved in the United States for the treatment of cataplexy or excessive daytime sleepiness in patients greater than or equal to 7 years of age with narcolepsy. The pharmacokinetics (PK) of SXB includes a negative food effect (reduced maximum plasma concentration [C-max] and area under the curve [AUC]) and greater than dose-proportional increase in exposure. WHAT QUESTION DID THIS STUDY ADDRESS? What are the relative bioavailability and bioequivalence of LXB and SXB in the fasted state, and how is the PK of LXB affected by food? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? At equivalent oxybate doses, in the fasted state, LXB had a lower C-max, delayed time to Cmax, and similar AUC versus SXB (bioequivalence criteria met for AUC). Cmax and AUC were lower under fed conditions (LXB and SXB); reduction in Cmax with food was less for LXB compared with SXB. Lower oxybate Cmax was associated with lower incidence of nausea and vomiting. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? PK differences between LXB and SXB may stem from reduced sodium. LXB represents a novel oxybate treatment for narcolepsy.