Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 34, Issue 1, Pages 91-94Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2009.01.008
Keywords
Voriconazole; Hepatotoxicity; Therapeutic drug monitoring; CYP2C19 polymorphism; Michaelis-Menten model
Funding
- Japan Society for the Promotion of Science [18923056]
- Grants-in-Aid for Scientific Research [18923056] Funding Source: KAKEN
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Voriconazole metabolism is mostly mediated via the cytochrome P450 (CYP) 2C19 isozyme. The non-wild (mutant) type of CYP2C19 is generally found in 60-70% of Asian populations. Because the voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity, this study investigated the effect of CYP2C19 polymorphism on the relationship between voriconazole trough concentrations and liver function abnormalities in 29 Japanese patients with fungal infections (CYP2C19 wild-type, n = 10; non-wild-type, n = 19). Hepatotoxicity, defined as liver enzyme abnormality according to the National Cancer Institute criteria, was observed in 10 (34.5%) of 29 patients with a trough concentration >= 3.9 mg/L. Logistic regression analysis suggested that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Non-linear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild-type and 4.4-6.5 mg/kg/day for the non-wild-type in Japanese patients. These recommended initial dosages and subsequent dose adjustment for the target concentration range by therapeutic drug monitoring should avoid adverse events and thus enable continued effective voriconazole therapy for Japanese patients with mycoses. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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