Characterization of the Pharmacokinetics of Samidorphan in Healthy Volunteers: Absolute Bioavailability and the Effect of Food and Age

BACKGROUND AND OBJECTIVES: Samidorphan (SAM) is a novel μ-opioid receptor antagonist. We report clinical pharmacokinetic (PK) properties of SAM following different routes of administration, and the effects of food and age on the PK of SAM following oral administration in healthy volunteers. METHODS: An open-label, fixed-sequence study (study 1, N = 10) examined the PK parameters following intravenous, sublingual, and oral exposure to SAM to determine absolute bioavailability. A double-blind, placebo-controlled study (study 2, N = 45) compared the PK in participants aged 18–40 years (cohort 1, n = 30) and ≥ 65 years (cohort 2, n = 15) who received a single oral dose of SAM 10 mg under fed (cohort 1 only) or fasted conditions. RESULTS: In study 1, intravenous SAM had a plasma clearance of 33.7 L/h, volume of distribution of 341 L, and elimination half-life of 7–8 h. SAM was well-absorbed following sublingual or oral administration and reached peak concentrations (C(max)) within 2 h, with absolute bioavailability of 71% (sublingual) and 69% (oral). In study 2, concentration–time profiles were similar under fed and fasted conditions (cohort 1) and for young and elderly participants from both cohorts; 90% confidence intervals for the geometric least squares mean ratios for C(max) and area under the concentration–time curve from time zero extrapolated to infinity indicated equivalence. CONCLUSIONS: SAM has high bioavailability that is comparable following sublingual and oral administration and is not subject to extensive first-pass metabolism. The PK of orally administered SAM are not affected by food or age.