Pharmacokinetics of Sublingual Buprenorphine Tablets Following Single and Multiple Doses in Chinese Participants With and Without Opioid Use Disorder.

Abstract

BackgroundTwo phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants.MethodsIn the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests.ResultsThe pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75–1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed.ConclusionsThe present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing.Clinical Trial RegistrationThe protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).Electronic supplementary materialThe online version of this article (10.1007/s40268-019-0277-9) contains supplementary material, which is available to authorized users.