Rifampicin decreases exposure to sublingual buprenorphine in healthy subjects

Buprenorphine is mainly metabolized by the cytochrome P450 (CYP) 3A4 enzyme. The aim of this study was to evaluate the role of first‐pass metabolism in the interaction of rifampicin and analgesic doses of buprenorphine. A four‐session paired cross‐over study design was used. Twelve subjects ingested either 600 mg oral rifampicin or placebo once daily in a randomized order for 7 days. In the first part of the study, subjects were given 0.6‐mg (placebo phase) or 0.8‐mg (rifampicin phase) buprenorphine sublingually on day 7. In the second part of the study, subjects received 0.4‐mg buprenorphine intravenously. Plasma concentrations of buprenorphine and urine concentrations of buprenorphine and its primary metabolite norbuprenorphine were measured over 18 h. Adverse effects were recorded. Rifampicin decreased the mean area under the dose‐corrected plasma concentration–time curve (AUC (0–18)) of sublingual buprenorphine by 25% (geometric mean ratio (GMR): 0.75; 90% confidence interval (CI) of GMR: 0.60, 0.93) and tended to decrease the bioavailability of sublingual buprenorphine, from 22% to 16% (P = 0.31). Plasma concentrations of intravenously administered buprenorphine were not influenced by rifampicin. The amount of norbuprenorphine excreted in the urine was decreased by 65% (P < 0.001) and 52% (P < 0.001) after sublingual and intravenous administration, respectively, by rifampicin. Adverse effects were frequent. Rifampicin decreases the exposure to sublingual but not intravenous buprenorphine. This can be mainly explained by an enhancement of CYP3A‐mediated first‐pass metabolism, which sublingual buprenorphine only partially bypasses. Concomitant use of rifampicin and low‐dose sublingual buprenorphine may compromise the analgesic effect of buprenorphine.