title: Correlation between voriconazole trough plasma concentration and hepatotoxicity in patients with different CYP2C19 genotypes.
abstract: 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 > or = 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 4.4-6.5mg/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.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Kazuro
authors.initials: K
authors.lastname: Ikawa
authors.forename: Kazuko
authors.initials: K
authors.lastname: Abematsu
authors.forename: Naoko
authors.initials: N
authors.lastname: Fukunaga
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nishida
authors.forename: Tomohide
authors.initials: T
authors.lastname: Fukamizu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shimodozono
authors.forename: Norifumi
authors.initials: N
authors.lastname: Morikawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005838:Genotype; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry*; D011110:Polymorphism, Genetic; D011743:Pyrimidines / Q000009:adverse effects*; D014230:Triazoles / Q000009:adverse effects*; D065819:Voriconazole
chemical_list: D011743:Pyrimidines; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole