Effect of ketoconazole on the pharmacokinetic profile of buprenorphine following administration of a once-weekly buprenorphine transdermal system.

BACKGROUND AND OBJECTIVE

Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10 μg/hour (BTDS 10).

METHODS

This single-centre study enrolled 20 healthy subjects who had demonstrated ketoconazole-mediated CYP3A4 inhibition via an erythromycin breath test. Subjects were randomized into a placebo-controlled, two-treatment, two-period crossover study. Subjects participated in a 7- to 14-day screening period, two baseline evaluations (day 0 [period 1] and day 16 [period 2]), two 12-day treatment periods (periods 1 and 2) separated by a 4-day washout period, and a study completion visit. Subjects received one BTDS 10 for 7 days per treatment period, administered concomitantly with either ketoconazole 200 mg twice daily or matching placebo. The main outcome measures were the ratios of geometric means for area under the plasma drug concentration versus time curve (AUC) from time zero to time of last measurable concentration (AUC(last)), AUC from time zero to infinity (AUC(∞)), and maximum plasma drug concentration (C(max)).

RESULTS

The ratio of geometric means (BTDS 10 with ketoconazole/BTDS 10 with placebo) was 99.4 (90% confidence interval [CI] 87.2, 113.3) for AUC(last) and 97.8 (90% CI 87.7, 109.1) for C(max). The ratio of geometric means for AUC(∞) was 86.7 (90% CI 70.7, 106.2). The plasma concentrations of the metabolites norbuprenorphine and norbuprenorphine-3β-glucuronide were slightly elevated following ketoconazole administration. BTDS 10 with ketoconazole was well tolerated and no apparent safety concerns were noted.

CONCLUSION

The lack of a clinically significant CYP3A4 interaction with ketoconazole following transdermal delivery of buprenorphine is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects. Metabolism of buprenorphine during therapy with BTDS is also not expected to be affected by co-administration of other CYP3A4 inhibitors.