Methadone Dosing & Nelfinavir, Nevirapine, & Efavirenz

6th Report from: 7th Conference on Retroviruses and Opportunistic Infections, San Francisco, Tuesday Feb 1

Methadone Dosing & Nelfinavir, Nevirapine, & Efavirenz

Although elfinavir reduced methadone blood levels, it appears as though no dose was necessary

Efavirenz and nevirapine reduce methadone blood levels, and methadone dose needs increase, but increase can be done incrementally

Pharmacokinetic (PK) and Pharmacodynamic (PD) Interactions between Nelfinavir and Methadone.

P. H. HSYU*^{1}, J. H. LILLIBRIDGE^{1}, L. MAROLDO^{2}, W. R. WEISS^{1}, and B. M. KERR^{1}. ^{1}Agouron Pharmaceuticals, Inc., San Diego, CA and ^{2}West Midtown Med. Group, New York.

Approximately 24% of HIV/AIDS patients are drug users. Both NFV and methadone (MD) are metabolized via cytochrome P450 enzymes and may have PK interactions that require dose adjustment for MD. The purpose of this study was to evaluate the PK and PD effects of NFV on maintenance MD regimen.

Fourteen subjects were enrolled in a prospective study. MD dose (10-140 mg/day) was stabilized and fixed for at least 1 month before NFV (1250 mg BID for 8 days) was added. Concentrations of MD enantiomers and their major metabolites ((+) and (-)-EDDP) were measured before and during NFV treatment. Concentrations of NFV and its active metabolite M8 were measured during NFV regimen. Adverse events (AE) and withdrawal /intoxication symptoms were monitored through the study. Case histories of 36 subjects who were maintained with stable MD dose (20-110 mg/day) were reviewed before and after addition of NFV (750 mg TID or 1250 mg BID from 3 to 105 weeks) retrospectively for withdrawal /intoxication symptoms and any dosing changes in MD prior to and during NFV treatment.

In the prospective study, NFV reduced the levels of (+)-MD, (-)-MD, (+)-EDDP, and (-)-EDDP by 47%, 39%, 29%, and 34%, respectively. However, none of the patients showed any withdrawal symptoms during the study or required dose adjustment during and after the study. NFV and M8 levels were within the normal range of historical data. Of the 36 patients in the retrospective study, 34 had unchanged dose of MD and reported no withdrawal or intoxication symptoms while receiving NFV. One patient required an increase in MD dose from 70 to 80 mg/day, and one patient voluntarily reduced MD dose from 30 mg to 20 mg/day.

The authors concluded that treatment with NFV appeared to have no impact on the maintenance dose of MD, although NFV reduced the levels of MD.

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Managing Methadone and Non-Nucleoside Reverse Transcriptase Inhibitors: Guidelines for Clinical Practice.

S. Clarke^{1}, F. Mulcahy^{1}, D. Back^{2}, S. Gibbons^{2}, J. Tjia^{2}, and M. Barry^{1}. ^{1}St. James's Hosp., Dublin, Ireland and ^{2}Univ. of Liverpool, UK.

Nevirapine and Efavirenz are potent inducers of the Cytochrome P450 enzyme system, and anecdotal reports suggest they may produce symptoms of methadone withdrawal when prescribed to injection drug users on methadone maintenance therapy. Two studies were designed to determine the pharmacokinetics of methadone when combined with either EFV or NVP.

Twenty five patients receiving stable methadone maintenance therapy were studied. All commenced ART with dual NRTI's and either EFV(n=15) or NVP(n=10). Pharmacokinetics before and two to three weeks (pending the onset of withdrawal symptoms) after initiating 600mgs EFV or NVP 200-400mgs OD were determined. Blood samples were obtained at times 0,1,2,3,4,5,6,7,8, and 24 hours post dosing.

When EFV was combined with methadone, there was a decrease in the mean maximum plasma concentration of methadone from 689 (range 212-1568) to 358 (205-706) ng/ml; p=0.007, 95% CI 112 to 549. The mean AUC {0-24h} for methadone also significantly reduced in the presence of EFV from 12341 (range 3682-34147) to 5309 (2430-10349) ng.h/ml; p=0.011, 95%, CI 1921 to 12143. Initial data on the interaction between NVP and methadone shows a mean reduction in AUC {0-24h} for methadone of 46% (range 23-80%). Seventeen patients complained of symptoms consistent with methadone withdrawal from day 8-10 onward, requiring a mean increase in methadone dose of 21.65% (mean increase 16 mg, range 15-30 mg).

An immediate increase and a substantial increase in methadone is therefore not appropriate as during the first 1-2 weeks of therapy there appears to be a process of 'induction -detoxification' whereby the increase in methadone dose required is not as great as might be expected from an individual's pharmacokinetic data. We recommend frequent medical assessments for such patients to monitor withdrawal symptoms, increasing methadone dose in increments of 10mgs from day 8-10 onwards.