Tipranavir/Ritonavir Induction of Buprenorphine Glucuronide Metabolism in HIV-Negative Subjects Chronically Receiving Buprenorphine/Naloxone

Background: Previous reports on the pharmacokinetic of tipranavir (TPV) and buprenorphine (BUP)/naloxone found that coadministration resulted in an 80% reduction in the area under the curve AUC of the primary BUP metabolite, norBUP, without any pharmacodynamic consequences. This study was conducted to characterize how tipranivir/ritonavir effects the glucuronide metabolites of BUP and may explain the reduction in the norBUP. Methods: HIV-seronegative subjects stabilized on at least 3 weeks of BUP/naloxone sequentially underwent baseline and steady-state pharmacokinetic evaluation of twice daily TPV 500 mg coadministered with ritonavir 200 mg (TPV/r). Results: Twelve subjects were enrolled and ten completed the study. The steady-state pharmacokinetics for BUP-3-glucuronide (BUP-3G) and norBUP-3-glucuronide (norBUP-3G) in the presence and absence of steady-state TPV/r were analyzed. The C(max) of BUP-3G was 8.78 +/- 5.23 ng/mL without TPV/r and increased to 12.7 +/- 11.7 after steady state of TPV/r was achieved. The AUC of BUP-3G was 31.1 +/- 19.4 (ng/mL) (h) without TPV/r and increased to 58. 6 +/- 49.5 after steady state of TPV/r was achieved (p = .0966). In contrast, steady-state norBUP-3G AUC(0-24 h) (p = .0216) and C(max) (p = .0088) were significantly decreased in the presence of steady-state TPV/r. Conclusions and Scientific Significance: This study further elucidates the effects of TPV/r on glucuronidation. The current evaluation of glucuronide metabolites of BUP and norBUP are suggestive of combined inhibition of Uridine diphosphate (UDP)-glucuronosyltransferase of the 1A family and cytochrome P450 3A4 that spares UGT2B7 leading to a shunting of BUP away from production of norBUP and toward BUP-3G as seen by a statistically significant increase in the AUC of BUP-3G.