Lack of effect of CYP3A4 inhibitor ketoconazole on transdermally administered buprenorphine

Abstract

Objective To evaluate the effect of ketoconazole on the pharmacokinetics of buprenorphine and its metabolites following application of a 10-mg buprenorphine transdermal system (BTDS). Methods This was a randomized, double-blind, 2-treatment, 2-period crossover study with 20 healthy male and female subjects. Treatments: BTDS for 7 days with ketoconazole (200 mg po, bid) or placebo in crossover fashion. Results The 90% confidence intervals for the estimated ratios of population geometric means for buprenorphine AUCt and Cmax were within 80% to 125%. Plasma concentrations of norbuprenorphine, and norbuprenorphine glucuronide, were detected in both treatments and were not lower in the BTDS+ ketoconazole treatment. Plasma concentrations of buprenorphine-3-glucuronide were measurable in 5 out of 18 BTDS+ ketoconazole subjects. No apparent safety concerns were identified. Eight subjects had hyperpigmentation at the application site (4 events were resolved and 4 were continuing). Conclusions Plasma concentrations of buprenorphine from BTDS did not differ during co-medication with ketoconazole 200 mg bid vs. placebo. BTDS dose adjustment is not needed for subjects taking concomitant CYP3A4 inhibitors. Clinical Pharmacology & Therapeutics (2005) 77, P78–P78; doi: 10.1016/j.clpt.2004.12.188