title: Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.
abstract: The aim of this study was to determine an optimum voriconazole target concentration, to study the influence of CYP2C19 gene status on metabolism of voriconazole and to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism in patients with invasive fungal infections. A total of 328 voriconazole trough plasma concentrations (C(min)) were collected and monitored from 144 patients. Information on efficacy and safety was obtained. Voriconazole therapy was effective in 81.9% of patients (118/144), and 12.5% (18/144) exhibited signs of hepatotoxicity. The relationships between voriconazole C(min) and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical C(min) range of 1.5-4 mg/L was identified. Values of voriconazole C(min) and the ratio of C(min) to concentration of voriconazole-N-oxide (C(min)/C(N)) of poor metabolisers (PMs) were significantly higher than extensive metabolisers and intermediate metabolisers. Model-based simulations showed that PM patients could be safely and effectively treated with 200 mg twice daily orally or intravenously, and non-PM patients with 300 mg twice daily orally or 200mg twice daily intravenously. This study highlighted that voriconazole C(min) and C(min)/C(N) are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity.
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Taotao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Tengzhou Central People's Hospital, Tengzhou 277500, China.
authors.forename: Huifang
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jinyao
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Limei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Central Intensive Care Unit, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: xajdxjf@mail.xjtu.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: dongyalin@mail.xjtu.edu.cn.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Dong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D016469:Fungemia / Q000188:drug therapy*; D006801:Humans; D008297:Male; D016921:Meningitis, Fungal / Q000188:drug therapy*; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D065819:Voriconazole / Q000009:adverse effects* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: CYP2C19; Efficacy; Hepatotoxicity; Safety; Trough plasma concentrations; Voriconazole