AAC Accepts, published online ahead of print on 30 October 2006

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00559-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

Ping Liu, Grover Foster, Robert LaBadie, Eugene Somoza, and Amarnath Sharma^*

Department of Clinical Pharmacology, and Department of Biostatistics, Pfizer Global Research and Development, Groton/New London, CT; New York office of Clinical Sciences, Pfizer Inc, NY; Cincinnati Addiction Research Center, VA Medical Center and Psychiatry Department, University of Cincinnati, Cincinnati, OH

^* To whom correspondence should be addressed. Email: AMARNATH.SHARMA{at}PFIZER.COM.

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 co-administration. Twenty-three patients on individualized methadone therapy (30 - 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 co-administer either 200 mg twice daily (BID) voriconazole (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 (AUC_0-24) by 47.2% (90% CI: 37.7%, 57.4%) and the mean peak concentration (C_max) by 30.7% (90% CI: 22.2%, 39.8%). The magnitude of increase in (S)-methadone exposure was greater than that of (R)-methadone: AUC_0-24: 103.4% (90% CI: 85.0%, 123.6%); C_max: 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 of voriconazole alone. Methadone patients receiving voriconazole showed no signs or symptoms of significant opioid withdrawal or overdose. Co-administration of 200 mg BID voriconazole with methadone was generally safe and well-tolerated. Nevertheless, caution should be exercised when voriconazole is co-administered with methadone due to the increase in (R)-methadone exposure, which in turn may require dose reduction of methadone.

This article has been cited by other articles:

• Reinhold, J. A, Sanoski, C. A, Russo, A. M, Cooper, J. M, Spinler, S. A (2009). Torsades de pointes associated with methadone and voriconazole. BMJ Case Reports 2009: bcr0720092119-bcr0720092119 [Abstract] [Full Text]  
• Jeong, S., Nguyen, P. D., Desta, Z. (2009). Comprehensive In Vitro Analysis of Voriconazole Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effect on CYPs 2B6, 2C9, 2C19, and 3A. Antimicrob. Agents Chemother. 53: 541-551 [Abstract] [Full Text]