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

Drug Alcohol Depend. 2009 Dec 1;105(3):234-9. doi: 10.1016/j.drugalcdep.2009.07.007. Epub 2009 Sep 1.

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(0-24h) and C(max) were 43.9 ng h/mL and 5.61 ng/mL, respectively. After achieving steady-state with TPV/r (> or = 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(0-24h) [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(0-12h) 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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Retroviral Agents / pharmacokinetics
  • Anti-Retroviral Agents / therapeutic use
  • Buprenorphine / pharmacokinetics*
  • Buprenorphine / therapeutic use
  • Drug Interactions
  • Drug Therapy, Combination / adverse effects
  • Female
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Seronegativity*
  • Humans
  • Male
  • Middle Aged
  • Naloxone / pharmacokinetics*
  • Naloxone / therapeutic use
  • Narcotic Antagonists / pharmacokinetics
  • Narcotic Antagonists / therapeutic use
  • Opioid-Related Disorders / complications
  • Opioid-Related Disorders / drug therapy
  • Pyridines / pharmacokinetics*
  • Pyridines / therapeutic use
  • Pyrones / pharmacokinetics*
  • Pyrones / therapeutic use
  • Ritonavir / pharmacokinetics*
  • Ritonavir / therapeutic use
  • Sulfonamides
  • Treatment Outcome

Substances

  • Anti-Retroviral Agents
  • Narcotic Antagonists
  • Pyridines
  • Pyrones
  • Sulfonamides
  • Naloxone
  • Buprenorphine
  • Ritonavir
  • tipranavir