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ICAAC 2012: Cobicistat-boosted Elvitegravir Does Not Interact with Methadone

The new HIV integrase inhibitor elvitegravir, boosted with cobicistat, does not cause clinically important changes in levels of methadone or buprenorphine used to manage opiate addiction, researchers reported at the recent 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012) in San Francisco.

The way drugs are processed in the liver can lead to interactions that raise or lower levels of one or both medications. Agents known as pharmacoenhancers, or "boosters," can raise concentrations of other drugs by interfering with their metabolism. Gilead's novel booster cobicistat inhibits activity of the CYP3A4 enzyme, which plays a role in processing many types of drugs including methadone and buprenorphine, used as maintenance substitution therapy for people trying to quit heroin or other opiates. Drug interactions could potentially lead to methadone or buprenorphine levels that are dangerously high or so low that they result in withdrawal symptoms.

Gilead has coformulated cobicistat with elvitegravir and the NRTIs tenofovir and emtricitabine in the recently approved Stribild single-tablet regimen. Approval of elvitegravir and cobicistat as single agents is pending before the FDA, and the company is working on an elvitegravir/cobicistat coformulation.

Because many people with HIV use opiate substitution therapy, Gilead scientists evaluated the potential for drug-drug interactions between cobicistat-boosted elvitegravir and methadone or the buprenorphine/naloxone coformulation (Suboxone). Prior research has shown that tenofovir and emtricitabine do not alter methadone or buprenorphine pharmacokinetics.

This study included participants on stable maintenance therapy using 80 mg to 120 mg methadone (Cohort 1, n= 12) or 16/4 mg to 24/6 mg buprenorphine/naloxone (Cohort 2, n=18). The researchers assessed pharmacokinetics after opiate dosing alone and after 10 days of co-administration of methadone or buprenorphine/naloxone with elvitegravir/cobicistat.

Results

• Methadone pharmacokinetics were unaffected by co-administration of elvitegravir/cobicistat.
• Buprenorphine and its metabolite norbuprenorphine reached modestly higher concentrations when administered with elvitegravir/cobicistat.
• No dose adjustments were needed for either methadone or buprenorphine/naloxone.
• Opiate substitutes also did not significantly affect elvitegravir or cobicistat levels, as pharmacokinetic parameters were comparable to historical data.
• Co-administration of methadone or buprenorphine with elvitegravir/cobicistat was generally well-tolerated.
• Common adverse events in both cohorts included nausea and headache (both about 20%).
• However, there were no study-drug related serious adverse events or drug discontinuations for this reason.

"No clinically relevant pharmacokineticand/or pharmacodynamicinteractions were observed between methadone or buprenorphine/naloxoneand elvitegravir/cobicistat," the researchers concluded. "[A]ccordingly, no dose adjustments are needed when these agents are coadministered with Stribild."

11/13/12

Reference

RD Bruce, P Winkle, J Custodio, S Ramanathan, et al. Pharmacokinetics of Cobicistat-Boosted Elvitegravir Administered in Combination with Methadone or Buprenorphine/Naloxone. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2012). San Francisco. September 9-12, 2012. Abstract A-1250.