073: A Phase 1, Randomized, Placebo-Controlled, Double-Blind, 2-Period, Fixed-Sequence Study to Assess the Relative Bioavailability & Safety of Low-Sodium Oxybate Between Japanese & Non-Asian Participants

Statement of Purpose, Innovation or Hypothesis: Calcium, magnesium, potassium and sodium oxybates, Xywav® (low-sodium oxybate [LXB]) oral solution is approved for the treatment of narcolepsy and idiopathic hypersomnia in the United States based on data in largely ( >98%) non-Asian participants. LXB has demonstrated rapid elimination with a half-life of < 1 hour, so the pharmacokinetics (PK) is similar after single or repeated dose administration. LXB is mainly cleared from the body via metabolism by gamma-hydroxybutyrate dehydrogenase and succinic semialdehyde dehydrogenase that are not known to be polymorphic so no metabolism-specific differences between non-Asians and Japanese ethnicity is expected. The objective of this study was to characterize PK and relative bioavailability in Japanese vs non-Asian healthy participants.
Description of Methods and Materials: This Phase 1 study assessed relative bioavailability and safety of LXB between Japanese (n=30; 24 on active, 6 on placebo) and body mass index (BMI)-, age-, and sex- matched non-Asian (n=30; 24 on active, 6 on placebo) participants at 2 single doses: 2.25 g and after a 48-hour washout, 4.5 g. The doses selected are reflective of how LXB is administered in clinical practice (patients may titrate from a low dose of 2.25 g twice nightly or 3.0 g once nightly to a therapeutically effective and tolerable dose of up to 4.5 g twice nightly or 6.0 g once nightly). PK parameters were determined using noncompartmental analysis with Phoenix WinNonlin v8.3. Statistical analyses of PK parameters were performed using SAS v9.4.
Data and

Results: LXB was rapidly absorbed (median Tmax: 0.64–1.00 hours) and eliminated (mean half-life: 0.506–0.614 hours) in both Japanese and non-Asian participants. The AUC0-∞ and Cmax in Japanese compared with non-Asian participants did not meet the bioequivalence criteria: 2.25 g (Cmax GMR [90% CI]: 123.61 [106.84, 143.02], AUC0-∞ GMR [90% CI]: 143.50 [114.08, 180.51]) and 4.5 g (Cmax GMR [90% CI]: 118.78 [101.94, 138.42], AUC0-∞ GMR [90% CI]: 131.90 [104.22, 166.93]). No apparent differences in adverse events (incidence and severity) were observed between groups at either dose.
Interpretation, Conclusion or Significance: Although BMI was matched across the 2 populations, non-Asian participants had a higher mean body weight compared with Japanese participants (73 vs 63 kg) and lower AUC0-∞ and Cmax; a higher body weight is associated with a higher clearance, thus a lower exposure of oxybate based on a prior population PK analysis. A sensitivity analysis was performed on PK parameters that were adjusted by weight-normalized dose; the relative bioavailability (Japanese vs non-Asian) at 2.25 and 4.5 g moved closer to 100% (more so for Cmax than for AUC): 2.25 g (Cmax GMR [90% CI]: 106.75 [92.42, 123.30], AUC0-∞ GMR [90% CI]: 123.93 [102.90, 149.25]) and 4.5 g (Cmax GMR [90% CI]: 102.44 [88.05, 119.18], AUC0-∞ GMR [90% CI]: 113.57 [93.62, 137.76]). Therefore, observed differences in exposure are unlikely clinically relevant because LXB is individually titrated based on balanced efficacy and tolerability per the USPI, which naturally takes body weight-related clearance differences into consideration.