H. Jia,1 M. K. Greenwald,2 B. D. Vince,3 P. J. Fudala,1 C. Heidbreder,1 A. F. Nasser1; 1Reckitt Benckiser Pharmaceuticals, Inc., Richmond, VA, 2Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences and Addiction Research Institute, Wayne State University, Detroit, MI, 3Vince & Associates Clinical Research, Inc., Overland Park, KS
BACKGROUND: RBP-6000 is a 28-day SC injection of depot buprenorphine (Bup). It was hypothesized (Nasser et al., 2014, J. CPK) that mu opioid receptor occupancy (RO) ≥ 70% and Bup plasma levels ≥ 2 ng/mL are needed to provide full blockade of opioid agonist effects. This study assessed RBP-6000 blockade of hydromorphone (HM) induced subjective and reinforcing effects.
METHODS: 39 subjects with opioid use disorder (not seeking treatment) first completed 3 HM challenges (0, 6, 18 mg IM on 3 consecutive days in randomized order), then 3 HM challenges at the end of 14-day SUBOXONE film stabilization. This was followed by two RBP-6000 300-mg doses separated by 28 days. For 12 weeks after the first RBP-6000 dose, on days 5-7 of each week, subjects received 3 HM challenges in randomized (6 sequences) order. A Drug Liking visual analog scale (VAS) score was the primary, and HM reinforcing effects (log breakpoint values), and VAS for Any Effect, Bad Effect, High, Good Effect, and Sedation were secondary endpoints. Statistical comparison using mixed effects model was used for each week. Change from HM 0 mg with 95% CI was reported, with a difference cut-off of ≤11 was required to declare full blockade. A PK sample was collected the morning of each HM administration day. A published Emax model was used to calculate RO.
RESULTS: For Drug Liking, mean differences for 6 or 18 mg HM compared to placebo were < 7 units on week 1 and decreased over the 12 weeks. After the second RBP-6000 injection, the 95% CI of the difference included 0. HM reinforcing effects and all VAS showed similar results. Bup concentrations were 1.8-3.7 ng/mL and RO 65-76% over the 12 weeks.
CONCLUSION: At 300 mg, RBP-6000 blocked HM subjective and reinforcing effects from weeks 1-12. The study results provide strong evidence for the further development of RBP-6000.