Interaction between buprenorphine and atazanavir or atazanavir/ritonavir

Abstract

Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n = 10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400 mg daily) or atazanavir/ritonavir (300/100 mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n = 10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p < 0.001, p < 0.001), norbuprenorphine (p = 0.026, p = 0.006), buprenorphine glucuronide (p = 0.002, p < 0.001), and norbuprenorphine glucuronide (NS, p = 0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

Introduction

Injection drug use continues to be a significant risk factor for HIV disease (Deany, 2000). The majority of injection drug users (IDUs) with HIV disease are opioid-dependent and in need of treatment for both HIV disease and substance dependence. Adherence to medical regimens among IDUs is often poor (Arnsten et al., 2002, Mehta et al., 1997). As a result, highly active antiretroviral therapy (HAART) is frequently underutilized in this population because of concerns regarding effective viral suppression (Celentano et al., 2001, Lucas et al., 2001, Strathdee et al., 1998). Treatment for opioid dependence that includes opioid-assisted therapy can promote adherence to HIV disease treatment regimens by stabilizing the chaotic lifestyle of the opioid-addicted individual. Studies have shown that the course of HIV disease in drug users receiving substance abuse treatment is similar to other groups with HIV infection (Cohn, 2002) and the rate of HIV progression can be slowed in IDUs who receive medical intervention (Cohn, 2002, Des Jarlais and Hubbard, 1999).

Methadone has been the most widely used opioid pharmacotherapy for the treatment of opioid dependence. However, its use has been associated with several adverse drug interactions with HIV therapeutics that can produce either elevated methadone concentrations with toxicity, or decreased methadone levels with withdrawal. Both effects may diminish adherence if uncorrected (Altice et al., 1999, McCance-Katz et al., 2002, McCance-Katz et al., 2003, McCance-Katz et al., 2004, McCance-Katz, 2005). Buprenorphine (BUP) has been shown to be equivalent to methadone in the treatment of opioid-dependent patients (Strain et al., 1996). Buprenorphine/naloxone (BUP/NLX) in a 4:1 ratio is the usual formulation used in the treatment of opioid dependence in the United States [McCance-Katz, 2004]. Naloxone, an opioid antagonist active only when administered parenterally, was added to BUP in a combination tablet to diminish diversion and abuse of the drug by injection (McCance-Katz, 2004). Further, the poor sublingual absorption of naloxone prevents its alteration of BUP opioid agonist effects. To date, BUP has not been shown to produce adverse drug interactions with delavirdine, efavirenz, nelfinavir, ritonavir (RTV) or lopinavir/ritonavir (McCance-Katz et al., 2006a, McCance-Katz et al., 2006b).

We now report on the interaction between BUP and a newer protease inhibitor (PI), atazanavir (ATV). Because in clinical practice many PIs are now administered in combination with RTV as a means of boosting PI plasma concentrations and simplifying HAART, a second study in which the interaction of BUP with atazanavir/ritonavir (ATV/r) was determined is also reported.