661. Use of Cimetidine to Increase Voriconazole Concentrations in a Patient with Suboptimal Voriconazole Exposure
Session: Abstracts: Mycology
Friday, October 22, 2010
Background: Voriconazole (VORI) is an azole antifungal that is metabolized by cytochrome P450 (CYP)2C9, CYP2C19, and CYP3A4. VORI concentrations have been associated with improved outcomes in fungal infections. It is therefore concerning that VORI exposure may decrease over time due to CYP-mediated autoinduction.  The CYP inhibitor cimetidine (CIM) may help maintain VORI concentrations by inhibiting its metabolism via CYP2C19 and CYP3A4.

Methods: A 22 year old African American male with an undiagnosed immunodeficiency presented with disseminated coccidioidomycosis that had failed to respond to ampho B, fluconazole, itraconazole and posaconazole.  Due to disease progression, the patient was switched to VORI and caspofungin. VORI was administered for 9 months in hospital, in which time, the patient’s dose requirement increased from 8 to 14 mg/kg/day. Due to difficulty in maintaining adequate concentrations, oral CIM was initiated and continued for five months. VORI levels (ng/mL) were divided by total daily VORI doses (mg) to yield dose-normalized VORI levels (ng/mL/mg of VORI administered). Dose-normalized VORI levels were then compared pre- and post CIM using a Student’s unpaired T-test. VORI concentrations were determined using HPLC/LC-MS.

Results: The average (geometric mean) dose-normalized VORI trough level prior to CIM initiation (n=8) was 0.59 ng/mL/mg; after CIM initiation (n=12), the average increased 2-fold to 1.26 ng/mL/mg (p=0.0015) (Figure below). The average dose-normalized peak VORI concentration was also significantly higher (1.5-fold) after CIM coadministration (p=0.008). VORI and CIM were well tolerated and the patient’s clinical condition stabilized.

Conclusion: VORI trough concentrations, normalized to total daily VORI dose, were increased 2-fold after the addition of oral CIM. The most likely mechanism for elevated voriconazole concentrations is the presence of CIM’s inhibition of voriconazole’s hepatic metabolism through CYP2C19 and CYP3A4. CIM may be useful as a pharmaco-enhancer to ensure therapeutic concentrations of voriconazole.


Subject Category: A. Antimicrobial agents and Resistance

Speakers:
Timothy J. Jancel, PharmD , Clinical Center Pharmacy, National Institutes of Health, Bethesda, MD
Scott Penzak, PharmD , Clinical Center Pharmacy, National Institutes of Health, Bethesda, MD
Alexandra F. Freeman, MD , National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD
Steven Holland, MD , National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, MD

Disclosures:

T. J. Jancel, None

S. Penzak, None

A. F. Freeman, None

S. Holland, None

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