title: Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block.
abstract: Sublingual buprenorphine formulations have been developed as treatments for opioid dependence. In three studies, opioid naïve 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 Cmax values ranged from 1.6 to 6.4 ng/ml and tmax 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). Cmax 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 Cmax 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 microg analgesic dose, was well tolerated in these opioid naïve subjects, as administration of naltrexone 50-150 mg was sufficient to attenuate anticipated adverse effects in this population of subjects.
authors.affiliation: Medeval Limited, Skelton House, Manchester Science Park, Lloyd Street North, Manchester M15 6SH, UK. smcaleer@medeval.com
authors.forename: Sarah D
authors.initials: SD
authors.lastname: McAleer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Mills
authors.forename: Torsten
authors.initials: T
authors.lastname: Polack
authors.forename: Tanweer
authors.initials: T
authors.lastname: Hussain
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rolan
authors.forename: Alan D
authors.initials: AD
authors.lastname: Gibbs
authors.forename: Frank G P
authors.initials: FG
authors.lastname: Mullins
authors.forename: Ziad
authors.initials: Z
authors.lastname: Hussein
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D002047:Buprenorphine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009271:Naltrexone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D009292:Narcotic Antagonists; D002047:Buprenorphine; D009271:Naltrexone