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Antimicrobial Agents and Chemotherapy, January 2007, p. 110-118, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00559-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Ping Liu,1 Grover Foster,3 Robert LaBadie,2 Eugene Somoza,4 and Amarnath Sharma1*

Department of Clinical Pharmacology,1 Department of Biostatistics, Pfizer Global Research and Development, New London, Connecticut,2 New York Office of Clinical Sciences, Pfizer Inc., New York, New York,3 Cincinnati Addiction Research Center, VA Medical Center and Psychiatry Department, University of Cincinnati, Cincinnati, Ohio4

Received 5 May 2006/ Returned for modification 9 August 2006/ Accepted 18 October 2006

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 (AUC0-24) was increased by 47.2% (90% confidence intervals [CI]: 37.7%, 57.4%), and the mean peak concentration (Cmax) 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 AUC0-24 was increased by 103.4% (90% CI: 85.0%, 123.6%), and the Cmax 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue, MS6025-A3237, New London, CT 06320. Phone: (860) 732-3217. Fax: (860) 686-5023. E-mail: amarnath.sharma{at}pfizer.com.

{triangledown} Published ahead of print on 30 October 2006.

Antimicrobial Agents and Chemotherapy, January 2007, p. 110-118, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00559-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • 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]  


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