Pharmacokinetic interaction between voriconazole and methadone at steady state in patients on methadone therapy

This trial was aimed to estimate the pharmacokinetic interaction between voriconazole and methadone at steady state in male patients on methadone therapy and to characterize the safety and tolerability profile during the coadministration. Twenty-three patients on individualized methadone therapy (30 to 100 mg once daily) were enrolled into this randomized, patient- and investigator-blind, placebo-controlled, parallel-group study. Methadone pharmacokinetic samples were collected from patients receiving methadone alone as the baseline before they were randomized to coadminister either 200 mg voriconazole twice daily (BID) (400-mg BID loading doses on the first day) (n = 16) or matching placebo (n = 7) for the next 5 days. Pharmacokinetic samples for methadone and voriconazole were collected on the last day of voriconazole dosing. The safety data were collected throughout the study. Voriconazole increased the steady-state exposure of pharmacologically active enantiomer (R)-methadone: the mean area under the concentration-time curve from 0 to 24 h (AUC(0-24)) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (C(max)) was increased by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: the AUC(0-24) was increased by 103.4% (90% CI: 85.0%, 123.6%), and the C(max) was increased by 65.4% (90% CI: 52.6%, 79.2%). Methadone appeared to have no effect on the steady-state voriconazole pharmacokinetics compared to the historical data for voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Coadministration of 200 mg voriconazole BID with methadone was generally safe and well tolerated. Nevertheless, caution should be exercised when voriconazole is coadministered with methadone due to the increase in (R)-methadone exposure, which in turn may require a dose reduction of methadone.