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

Abstract

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 µg/ml; study 2 [60 ml]: 94.6 vs. 123.0 μg/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 μg∙h/ml; AUC_0-∞ , 236.5 vs. 265.2 μg∙h/ml; study 2: AUC_0-t , 241.5 vs. 254.7 μg∙h/ml; AUC_0-∞ , 243.1 vs. 256.3 μg∙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.