Pharmacokinetic interactions between buprenorphine/naloxone and tipranavir/ritonavir in HIV-negative subjects chronically receiving buprenorphine/naloxone

Abstract

HIV-infected patients with opioid dependence often require opioid replacement therapy. Pharmacokinetic interactions between HIV therapy and opioid dependence treatment medications can occur. HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone (BUP/NLX) therapy sequentially underwent baseline and steady-state pharmacokinetic evaluation of open-label, twice daily tipranavir 500 mg co-administered with ritonavir 200 mg (TPV/r). Twelve subjects were enrolled and 10 completed the study. Prior to starting TPV/r, the geometric mean BUP AUC 0–24 h and C max were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (≥7 days), these values were similar at 43.7 ng h/mL and 4.84 ng/mL, respectively. Similar analyses for norBUP, the primary metabolite of BUP, demonstrated a reduction in geometric mean for AUC 0–24 h [68.7–14.7 ng h/mL; ratio = 0.21 (90% CI 0.19–0.25)] and C max [4.75–0.94 ng/mL; ratio = 0.20 (90% CI 0.17–0.23)]. The last measurable NLX concentration ( C last) in the concentration–time profile, never measured in previous BUP/NLX interaction studies with antiretroviral medications, was decreased by 20%. Despite these pharmacokinetic effects on BUP metabolites and NLX, no clinical opioid withdrawal symptoms were noted. TPV steady-state AUC 0–12 h and C max decreased 19% and 25%, respectively, and C min was relatively unchanged when compared to historical control subjects receiving TPV/r alone. No dosage modification of BUP/NLX is required when co-administered with TPV/r. Though mechanistically unclear, it is likely that decreased plasma RTV levels while on BUP/NLX contributed substantially to the decrease in TPV levels. BUP/NLX and TPV/r should therefore be used cautiously to avoid decreased efficacy of TPV in patients taking these agents concomitantly.