Day 3 Report from Lisbon European AIDS Conference

Oct 26, 10 pm
Jules Levin, NATAP

Efavirenz Reduces Methadone Levels.
Susan Clarke, David Back and others reported pharmacokinetics (blood levels) and tolerability from a study of 11 HIV+ individuals receiving methadone and efavirenz. EFV is both an inducer and inhibitor of cytochrome P450, the principal pathway through which methadone is metabolized. There had been anecdotal reports that EFV reduced methadone effectiveness but this is the first definitive PK study. 11 patients receiving stable methadone maintenance therapy (dose range 35-100 mg) enrolled in study and started HIV treatment with EFV + 2 nucleoside analogues. Methadone PK was determined before and after 3 weeks after starting EFV 600 mg daily. Blood samples were obtained at times 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post dosing.

Results
9 patients complained of symptoms consistent with methadone withdrawal, requiring a mean increase in methadone dose of 21.65% (mean increase 16 mg, range 15-30 mg). When EFV was combined with methadone, there was a marked decrease in the mean maximum plasma concentration of methadone from 689 (range 212-1568) to 358 (205-706) ng/ml (p=0.007).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).

Upon examination of graph of the reduction in methadone in all 11 patients, I observed individual variability. Remember the methadone doses for 11 people ranged from 35 to 100 mg. One patient had about 35000 methadone AUC 0-24h (ng/ml.n) prior to starting EFV and about 5000 after starting EFV. At the other extreme, a second person had about 3000 AUC 0-24 prior to starting EFV and the same level after EFV. A third person had about 12000 prior to EFV and about 2500 after EFV was added. A fourth person had similar numbers as the third person. Four individuals appeared to experience about a 50% reduction in methadone after adding EFV. I think it might be helpful to measure an individual’s methadone levels at the appropriate time after they start EFV to identify their response.

The authors concluded a reduction in plasma methadone concentrations is to be expected after starting EFV therapy. Once the dose of methadone is increased appropriately based on PK data and clinical evaluation, EFV is well tolerated by injection drug users.