Investigation of the Interactions between Methadone and Elvitegravir-Cobicistat in Subjects Receiving Chronic Methadone Maintenance

Abstract

cInteractions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, the R-methadone mean area under the concentration-time curve to the end of the dosing period (AUC tau ) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (C max ) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, the S-methadone mean AUC tau (7,040 versus 7,540 h · ng/ml) and mean C max (446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUC tau , C max , and C tau of elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

Cobicistat: a new opportunity in the treatment of HIV disease?

“…Also, the side effects of the anticancer agents dasatinib, nilotinib, vinblastine and vincristine are likely to increase as observed with conventionally boosted PIs, and the plasma concentrations of fluticasone and metformin may be increased. On the contrary, methadone levels are not affected by coadministration [16], and only minor interaction exists with buprenorphine and naloxone [17]. [20].…”

Comparative study of the neurotoxicological effects of tramadol and tapentadol in SH-SY5Y cells

“…Other authors have used high opioid concentrations in similar studies, such as that of Perez-Alvarez et al, who exposed SH-SY5Y cells to methadone concentrations up to 1000-fold its Cmax(Bruce et al 2013;Perez-Alvarez et al 2010). Regarding postmortem, tramadol and tapentadol concentrations are highly variable.…”

Darunavir/cobicistat once daily for the treatment of HIV

“…No dose adjustment of methadone is required [46] Buprenorphine/naloxone Cobicistat exposures consistent with historical data Buprenorphine: AUC tau : " 35%; C max : " 12%; C tau : " 66% Naloxone: AUC tau : # 28%; C max : # 28%…”

“…The combination of cobicistat with elvitegravir had only a modest effect on rosuvastatin exposure that was not clinically significant, allowing this combination to be used without dose adjustment [45]. Similarly, drug-drug interaction studies of cobicistat and elvitegravir combined with opioids showed no clinically significant effect on methadone, buprenorphine/naloxone or cobicistat [46,47].…”