Rocavorexant, a novel, selective orexin‐1 receptor antagonist: Safety, tolerability and pharmacokinetics in healthy adults and individuals with opioid use disorder

Aims Rocavorexant (INDV‐2000), a selective orexin‐1 receptor antagonist, reduces drug self‐administration and anxiety in nonclinical studies. This Phase 1 programme evaluated the safety, pharmacokinetics and pharmacodynamics of rocavorexant in healthy volunteers and treatment‐seeking individuals with opioid use disorder (OUD). Methods Two double‐blinded Phase I studies were conducted: a first‐in‐human, single‐ascending dose (SAD) study administering 1 to 720 mg under fasting condition with a food‐effect arm (360 mg, fasting vs . fed); and a multiple‐ascending dose (MAD) study evaluating up to 400 mg twice daily for up to 28 days in healthy volunteers, followed by an open‐label cohort enrolling individuals with OUD who received 400 mg twice daily during co‐administration with buprenorphine/naloxone and after discontinuation. Results Rocavorexant was rapidly absorbed with a mean plasma terminal half‐life of 2–5 h. Plasma exposure after single doses increased dose proportionally for the area under the curve (AUC 0‐inf ) and less than dose proportionally for maximum plasma concentration (C max ). A high‐fat meal increased rocavorexant C max by 62% (90% confidence interval [CI] of geometric mean ratio [GMR] 1.47–1.79) without affecting AUC 0‐inf (GMR 0.90; 90% CI: 0.74–1.10). Steady‐state was achieved by Day 2 with minimal accumulation. Buprenorphine/naloxone co‐administration increased rocavorexant AUC by 21% (GMR 90% CI: 1.01–1.45), with minor change in C max (GMR 1.10; 90% CI: 0.94–1.28). Rocavorexant was safe and well tolerated; somnolence was the most frequent adverse event. In the OUD cohort, rocavorexant helped manage opioid withdrawal following buprenorphine/naloxone discontinuation. Conclusion Rocavorexant demonstrated favourable safety, pharmacokinetic and pharmacodynamic characteristics supporting further clinical evaluation for OUD.