Pharmacokinetic Interaction between Voriconazole and Methadone at Steady State in Patients on Methadone Therapy

Abstract

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.

Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A

“…If the concentrations of voriconazole obtained after induction are taken into account in the determination of [I], the predicted AUC changes (1.4-to 6.4-fold) will be within the clinically observed range (37) ( Table 1). These data emphasize that the estimation of [I] should take bidirectional drug interactions into account, particularly when those interactions involve the induction of voriconazole metabolism, and that the intrinsic ability of voriconazole to alter the pharmacokinetics of substrate drugs primarily metabolized by CYP2B6 in a noninduced state is likely to be greater than what has been reported for efavirenz (37) and methadone (36) because of the induction of voriconazole metabolism by the former and the involvement of multiple enzymes in methadone elimination (14,63). Although CYP2B6 has been studied less than the other CYPs, a growing list of drugs have been identified as substrates of CYP2B6 (64).…”

“…Several clinical studies and case reports have documented that voriconazole substantially reduces the clearance of several drugs, including warfarin (49), phenytoin (48), midazolam (53), diazepam (52), immunosuppressant drugs (cyclosporine, sirolimus, and tacrolimus) (46,47), efavirenz (37), methadone (36), ibuprofen (27), diclofenac (26), fentanyl and alfentanil (54), oxycodone (22), and omeprazole (47). Considering the mechanisms of clearance of the drugs affected (3), many of these drug-drug interactions appear to be attributable to pharmacokinetic changes that can be understood in terms of inhibition of the cytochrome P450 (CYP) system.…”

Pharmacokinetic Effects of Isavuconazole Coadministration With the Cytochrome P450 Enzyme Substrates Bupropion, Repaglinide, Caffeine, Dextromethorphan, and Methadone in Healthy Subjects

“…In contrast to isavuconazole, voriconazole is associated with up to 2‐fold increases in R‐methadone exposure, which are attributed to CYP3A4 inhibition37 (see also VFEND ® package insert). Similar to isavuconazole, posaconazole does not inhibit CYP1A2, CYP2C8, or CYP2D6 activity 38.…”

Drug-Induced Arrhythmia

“…43 The sentinel historic example of this form of drug interaction is the concomitant use of terfenadine and inhibitors of the B, Recorded after 30 minutes of exposure to 10 g/mL erythromycin. C, Recorded 30 minutes after the concentration of erythromycin was increased to 100 g/mL.…”