Nevirapine Significantly Reduces the Levels of Racemic Methadone and ( R )-Methadone in Human Immunodeficiency Virus-Infected Patients

Abstract

Methadone is metabolized by various isoforms of the cytochrome P450 family, which can be induced by many drugs, including nevirapine. The objective of the present study was to determine the effects of coadministration of nevirapine and methadone on the dose-adjusted areas under the concentration-time curves (AUCs) of racemic and (R)-methadone. Twenty-five human immunodeficiency virus-infected subjects taking stable single daily doses of racemic methadone or (R)-methadone were included in this prospective, single-crossover trial. At the baseline, nevirapine was either started as part of a new regimen containing two nucleoside reverse transcriptase inhibitors (NRTIs) or added to an ongoing NRTI regimen. Patients could increase their methadone doses if withdrawal symptoms developed. Twelve-hour pharmacokinetic profiles were obtained before and 28 days after the start of nevirapine treatment. The total concentrations of methadone and its inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in serum were determined by liquid chromatography-tandem mass spectrometry. Among the 20 evaluable patients, coadministration of nevirapine significantly decreased the mean dose-adjusted AUC of methadone by 41%. AUC reductions were similar for patients taking racemic methadone (37%; n ‫؍‬ 11) and (R)-methadone (44%; n ‫؍‬ 9). AUC changes ranged from mild increases in three patients to decreases of up to 70%. Fourteen of 20 patients required additional methadone due to withdrawal symptoms. However, the median dose increase was only 15%, which was less than that which would have been expected from the pharmacokinetic data. The AUC of EDDP increased significantly, by 35%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine. Due to extensive variability, the adjustments must be tailored to the individual patient's needs.Human immunodeficiency virus (HIV)-infected patients who take methadone for the management of intravenous drug use frequently complain about symptoms of narcotic withdrawal after having started antiretroviral treatment containing nevirapine (NVP) (1,2,18,28,29). Symptoms rarely appear within the first few days, which suggests that the effect is caused by the induction of methadone metabolism by NVP (3, 11). One controlled trial involving eight patients has shown that concomitant NVP treatment substantially decreases the trough level and the area under the concentration-time curve (AUC) of methadone (11).Methadone is a racemic mixture of the pharmacodynamically inactive (S)-methadone and the active enantiomer (R)-methadone. It contains equal parts of both enantiomers. In some countries, methadone is frequently used in a formulation which contains only the active enantiomer, (R)-methadone. Both enantiomers are metabolized by members of the cytochrome P450 family. N-demethylation results in the formation of the inactive metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) (4, 30).NVP, a nonnucleoside inhibitor of the HIV reverse transcriptase,...

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“…Following nevirapine and efavirenz treatment, decreased levels of methadone were found 4-10 days later [19,20]. Thus, opiate withdrawal syndrome occurred and, consequently, either methadone dose was increased [6,[19][20][21][22][23][24] or antiretroviral treatment (nevirapine and efavirenz) discontinued [25].…”

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“…First line preferred NNRTIs, nevirapine [79][80][81] and efavirenz [82,83] induce methadone metabolism with resultant opioid withdrawal. Thus, the co-medication of methadone with first line regimens often requires elevations in methadone dosages.…”

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