A Long-acting Naltrexone Implant (iSTEP-N) for Opioid Use Disorder: First-in-Human Phase I Trial.

Abstract

iSTEP-N is a novel, bioresorbable, subcutaneous implant designed to release naltrexone for 6-12 months after a single procedure and improve adherence. This first-in-human study evaluated the safety and pharmacokinetics of iSTEP-N. This was a single-center, randomized, double-blind, placebo-controlled, single-ascending-dose trial. Sixteen healthy adults (6 females and 10 males) were assigned to receive either 1 implant (4.8 g naltrexone), 2 implants (9.6 g naltrexone), or placebo implants. Participants were followed for 12 weeks, after which implants were removed per regulatory requirement. Plasma naltrexone concentrations and safety outcomes were assessed throughout. All participants completed the study. The 9.6 g cohort maintained mean plasma naltrexone concentrations above the 2.0 ng/mL opioid blockade threshold from Tmax at 10 hours through the end of the study at 12 weeks; no mean value fell below 2.8 ng/mL during this time. The 4.8 g cohort maintained therapeutic levels of naltrexone through week 6 but dropped below threshold thereafter. In both cohorts, ∼22% of implant drug content was released over 12 weeks, based on plasma exposure and estimated clearance, indicating potential for extended coverage. In the 9.6 g group, seroma formation was observed in 3 of 6 participants (50%) and resolved without intervention. No serious adverse events occurred. At the 9.6 g dose, iSTEP-N provided sustained therapeutic naltrexone exposure for 12 weeks with a favorable safety profile, while releasing less than one-fourth of its drug content. Further studies will evaluate longer-term exposure, safety, and clinical feasibility in individuals with opioid use disorder.