Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naı̈ve healthy male volunteers under a naltrexone block

Abstract Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naive healthy male subjects received Subutex® tablets (buprenorphine 2 and 8 mg [ N =27] or 12 and 16 mg [ N =27]) or Suboxone® (two formulations) tablets (buprenorphine 8 mg/naloxone 2 mg [ N =36]) sublingually, under a naltrexone block for assessment of buprenorphine pharmacokinetics and tablet disintegration times. Plasma buprenorphine was quantified up to 72 h post-dose using a sensitive LC–MS/MS assay. Mean C max values ranged from 1.6 to 6.4 ng/ml and t max from 0.5 to 3 h. Concentrations declined bi-exponentially and fluctuations after a meal suggested enterohepatic recirculation of buprenorphine. The terminal half-life was approximately 26 h (range 9–69). C max and AUC appeared to increase in proportion to Subutex® dose over 8–16 mg. The Suboxone® formulations were bioequivalent. The least squares mean (90% CI) treatment ratio for C max was 1.00 (0.92–1.10) and AUC was 1.00 (0.95–1.06). Median times of disintegration were similar for all doses and formulations (range 6–12 min). Sublingual buprenorphine, up to 40 times the 400 μg analgesic dose, was well tolerated in these opioid naive subjects, as administration of naltrexone 50–150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects.