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Antimicrobial Agents and Chemotherapy, September 2006, p. 3227-3228, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00551-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Safety of Voriconazole in a Patient with CYP2C9*2/CYP2C9*2 Genotype


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Voriconazole, a broad-spectrum triazole antifungal agent, is well absorbed, with a high oral bioavailability of 96% (6). Maximal plasma concentrations are observed 1 to 2 h after drug administration. The volume of distribution is estimated to be 4.6 liters/kg, and the plasma protein binding is 58%. A terminal elimination half-life (t1/2) of 8 h in CYP2C19 extensive metabolizers (EMs) and a t1/2 of 15 h in CYP2C19 poor metabolizers (PMs) were reported (4). Due to a possible saturation of metabolism, voriconazole exhibits nonlinear pharmacokinetics (6). The main metabolite is voriconazole N oxide, which is formed by CYP2C19, CYP3A4, and to a lesser extent CYP2C9 (2).

CYP2C19 is a polymorphically expressed enzyme, with 2.2% of the Caucasian population being PMs (9) with a genetically determined absence of active enzyme. It is known that voriconazole pharmacokinetics are substantially influenced by the CYP2C19 genotype (4, 7). A reduction of voriconazole metabolic clearance in PMs of CYP2C19 is expected; data published so far indicate approximately threefold higher voriconazole area-under-the-concentration-time-curve or maximum-concentration-of-drug-in-serum values in CYP2C19 PMs than in homozygous EMs (4, 7).

Two common allelic variants of CYP2C9 have a markedly reduced catalytic activity (about 20% for CYP2C9*2 and less than 10% for CYP2C9*3) compared with that of the wild-type enzyme (CYP2C9*1) (3). Accordingly, PMs have an impaired metabolism of phenytoin, tolbutamide, glipizide, and warfarin, although PMs are very uncommon (0.2 to 1.0% of Caucasians but essentially 0% of Southeast Asians) (10). So far no in vivo data are available on the influence of CYP2C9 genetic polymorphism on voriconazole pharmacokinetics.

An ongoing study on the pharmacokinetics of voriconazole patients included those who had received their oral loading dose of voriconazole (400 mg) as a regular therapeutic drug treatment during hospitalization and a 12-h (dosing interval) pharmacokinetic profile after the first dose was obtained. We identified one Caucasian patient as a homozygous carrier of the CYP2C9*2 allele, using an established genotyping method using real-time fluorescence PCR on a LightCycler (Roche, Mannheim, Germany) (1). Additionally, the CYP2C19 genotype was also determined, which was homozygous for the wild-type allele (CYP2C19*1/CYP2C19*1). Plasma voriconazole concentrations were determined in the reference laboratory at Heidelberg University using a fully validated high-pressure liquid chromatography (HPLC) assay as described elsewhere (5, 8). Noncompartmental pharmacokinetic parameters were calculated using WinNonlin 4.1 (Pharsight, Mountain View, CA).

We compared the obtained pharmacokinetic parameters with those from an earlier study with volunteers whose CYP2C9 and CYP2C19 genotypes were characterized (4). In our patient, the apparent oral clearance (Cl/F), area under the concentration-time curve from zero hours to infinity (AUC0-{infty}), volume of distribution (Vz), and t1/2 values for voriconazole were not different from those of CYP2C9 EMs who were also CYP2C19 EMs after a single oral dose of 400 mg voriconazole (4) (shown in Table 1).


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  		TABLE 1. Pharmacokinetic parameters after administration of 400 mg voriconazole as a single oral dose in a CYP2C9*2/CYP2C9*2 patient (CYP2C19 homozygous EM) compared to results for eight CYP2C9 EM healthy volunteers (CYP2C19 homozygous EM)

 
A conclusion could be that a reduced-metabolizer status of CYP2C9, and therefore low catalytic activity of the enzyme, does not alter the pharmacokinetics of voriconazole. From our data it can be supported that CYP2C9 plays only a minor role in the elimination (metabolism) of voriconazole.


   ACKNOWLEDGMENTS
 
We are grateful to Johanna Weiss for the genotype analysis and for the excellent technical assistance of Jutta Kocher and Andrea Deschlmayr during analytical procedures.

The Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, has received a grant from Pfizer, New York, to establish and make available an HPLC method for the determination of voriconazole in plasma which is validated according to Food and Drug Administration standards.

None of the authors has financial or personal relationships that could potentially be perceived as influencing the research described herein.


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  1. Burian, M., S. Grosch, I. Tegeder, and G. Geisslinger. 2002. Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br. J. Clin. Pharmacol. 54:518-521.[CrossRef][Medline]
  2. Hyland, R., B. C. Jones, and D. A. Smith. 2003. Identification of the cytochrome P450 enzymes involved in the N-oxidation of voriconazole. Drug Metab. Dispos. 31:540-547.[Abstract/Free Full Text]
  3. Lee, C. R., J. A. Goldstein, and J. A. Pieper. 2002. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 12:251-263.[CrossRef][Medline]
  4. Mikus, G., V. Schöwel, M. Drzewinska, J. Rengelshausen, R. Ding, K. D. Riedel, J. Burhenne, J. Weiss, T. Thomsen, and W. E. Haefeli. Potent CYP2C19 genotype related interaction between voriconazole and the CYP3A4 inhibitor ritonavir. Clin. Pharmacol. Ther., in press.
  5. Pennick, G. J., M. Clark, D. A. Sutton, and M. G. Rinaldi. 2003. Development and validation of a high-performance liquid chromatography assay for voriconazole. Antimicrob. Agents Chemother. 47:2348-2350.[Abstract/Free Full Text]
  6. Purkins, L., N. Wood, P. Ghahramani, K. Greenhalgh, M. J. Allen, and D. Kleinermans. 2002. Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrob. Agents Chemother. 46:2546-2553.[Abstract/Free Full Text]
  7. Rengelshausen, J., M. Banfield, K. D. Riedel, J. Burhenne, J. Weiss, T. Thomsen, I. Walter-Sack, W. E. Haefeli, and G. Mikus. 2005. Opposite effects of short-term and long-term St John's wort intake on voriconazole pharmacokinetics. Clin. Pharmacol. Ther. 78:25-33.[CrossRef][Medline]
  8. Shah, V. P., K. K. Midha, J. W. Findlay, H. M. Hill, J. D. Hulse, I. J. McGilveray, G. McKay, K. J. Miller, R. N. Patnaik, M. L. Powell, A. Tonelli, C. T. Viswanathan, and A. Yacobi. 2000. Bioanalytical method validation—a revisit with a decade of progress. Pharm. Res. 17:1551-1557.[CrossRef][Medline]
  9. Shimizu, T., H. Ochiai, F. Asell, H. Shimizu, R. Saitoh, Y. Hama, J. Katada, M. Hashimoto, H. Matsui, K. Taki, T. Kaminuma, M. Yamamoto, Y. Aida, A. Ohashi, and N. Ozawa. 2003. Bioinformatics research on inter-racial difference in drug metabolism. I. Analysis on frequencies of mutant alleles and poor metabolizers on CYP2D6 and CYP2C19. Drug Metab. Pharma-cokinet. 18:48-70.[CrossRef][Medline]
  10. Wilkinson, G. R. 2005. Drug metabolism and variability among patients in drug response. N. Engl. J. Med. 352:2211-2221.[Free Full Text]
Marcus J.P. Geist
Department of Internal Medicine VI
Clinical Pharmacology and Pharmacoepidemiology
University of Heidelberg
Im Neuenheimer Feld 410
D-69120 Heidelberg, Germany,1

Gerlinde Egerer
Department of Internal Medicine V
Haematology, Oncology and Rheumatology
University of Heidelberg
Im Neuenheimer Feld 410
D-69120 Heidelberg, Germany,2

Jürgen Burhenne
Gerd Mikus*

* Phone: 49 6221 56 39197, Fax: 49 6221 56 4642, E-mail: gerd.mikus{at}med.uni-heidelberg.de

Antimicrobial Agents and Chemotherapy, September 2006, p. 3227-3228, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00551-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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