title: 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(0-24h) 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.
authors.affiliation: Yale University AIDS Program, 135 College Street, Suite 323, New Haven, CT, United States. Robert.bruce@yale.edu
authors.forename: R Douglas
authors.initials: RD
authors.lastname: Bruce
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Altice
authors.forename: David E
authors.initials: DE
authors.lastname: Moody
authors.forename: Shen-Nan
authors.initials: SN
authors.lastname: Lin
authors.forename: Wenfang B
authors.initials: WB
authors.lastname: Fang
authors.forename: John P
authors.initials: JP
authors.lastname: Sabo
authors.forename: Jan M
authors.initials: JM
authors.lastname: Wruck
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Piliero
authors.forename: Carolyn
authors.initials: C
authors.lastname: Conner
authors.forename: Laurie
authors.initials: L
authors.lastname: Andrews
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Friedland
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D002047:Buprenorphine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy; D018023:HIV Seronegativity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000493:pharmacokinetics* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use; D009293:Opioid-Related Disorders / Q000150:complications / Q000188:drug therapy; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011753:Pyrones / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents; D009292:Narcotic Antagonists; D011725:Pyridines; D011753:Pyrones; D013449:Sulfonamides; D009270:Naloxone; D002047:Buprenorphine; D019438:Ritonavir; C107201:tipranavir