ABSTRACT
BACKGROUND: Interactions between human immuno-deficiency virus (HIV) and opioid-dependence therapies can occur. OBJECTIVES: We sought to determine whether such interactions occurred between buprenorphine/naloxone and raltegravir. METHODS: We performed a within-subject open-labeled pharmacokinetic and pharmacodynamic study in 12 HIV-seronegative subjects stabilized on at least 3 weeks of buprenorphine/naloxone therapy. Subjects underwent baseline and steady-state evaluation of the effect of raltegravir 400 mg BID on buprenorphine/naloxone parameters. RESULTS: Compared with baseline values, buprenorphine AUC(0-24 h) (58.2 vs. 56.0 hr*ng/mL) and C(max) (7.37 vs. 6.60 ng/mL) did not differ significantly after achieving steady-state raltegravir. Similar analyses of norbuprenorphine, the primary metabolite of buprenorphine, demonstrated no significant difference after raltegravir administration. Naloxone concentrations were unchanged for AUC(0-24 h) (.595 vs. .581 hr*ng/mL), C(max) (.251 vs. .243 ng/mL) and T(max) (.75 vs.1.08 h). Objective opioid withdrawal was not observed. The AUC(0-12 h) and C(max) of raltegravir did not significantly differ from historical controls (5543 vs. 4428 h*ng/mL and 1070 vs. 1266 ng/mL), respectively. CONCLUSION: The addition of raltegravir to stabilized patients receiving buprenorphine/naloxone does not significantly affect buprenorphine/naloxone or raltegravir pharmacokinetic or pharmacodynamic parameters.
Subject(s)
Antiviral Agents/pharmacokinetics , Buprenorphine/pharmacokinetics , Naloxone/pharmacokinetics , Pyrrolidinones/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Buprenorphine/administration & dosage , Buprenorphine/adverse effects , Drug Combinations , Drug Interactions , Female , Glucuronosyltransferase/antagonists & inhibitors , HIV Seronegativity , Humans , Male , Middle Aged , Naloxone/administration & dosage , Naloxone/adverse effects , Narcotic Antagonists/administration & dosage , Narcotic Antagonists/adverse effects , Narcotic Antagonists/pharmacokinetics , Opiate Substitution Treatment/adverse effects , Pyrrolidinones/adverse effects , Raltegravir Potassium , Substance Withdrawal Syndrome/diagnosisABSTRACT
AIMS: Gender differences are known to occur in the pharmacokinetics of many drugs. Mechanisms may include differences in body composition, body weight, cardiac output, hormonal status, and use of different co-medications. Recently subtle gender-dependent differences in cytochrome P450 (CYP) 3A-dependent metabolism have been demonstrated. Buprenorphine N-dealkylation to norbuprenorphine is primarily performed by CYP3A. We therefore asked whether gender-dependent differences occur in the pharmacokinetics of buprenorphine. METHODS: A retrospective examination was made of control (buprenorphine/naloxone-only) sessions from a number of drug interaction studies between buprenorphine and antiretroviral drugs. Twenty males and eleven females were identified who had a negative cocaine urine test prior to participation in the control session and were all on the same maintenance dose (16/4 mg) of sublingual buprenorphine/naloxone. Pharmacokinetic data from their control sessions (buprenorphine/naloxone only) were sorted by gender and compared using the two-sample t-test. RESULTS: Females had significantly higher area under the plasma concentration curve (AUC) and maximum plasma concentrations for buprenorphine, norbuprenorphine and norbuprenorphine-3-glucuronide. AUCs relative to dose per body weight and surface area were significantly higher for only norbuprenorphine. AUCs relative to lean body mass were, however, not significantly different. CONCLUSIONS: Gender-related differences exist in the pharmacokinetics of buprenorphine; differences in body composition appear to have a major impact; differences in CYPA-dependent metabolism may also contribute.
