title: Impact of CYP2C19 genetic polymorphisms on voriconazole dosing and exposure in adult patients with invasive fungal infections.
abstract: Voriconazole (VCZ) use is limited by its narrow therapeutic range and significant interpatient variability in exposure. This study aimed to assess (i) the impact of CYP2C19 genotype on VCZ exposure and (ii) the doses required to achieve the therapeutic range in adult patients with invasive fungal infections (IFIs). Therapeutic drug monitoring (TDM) of VCZ, based on trough concentration measurement, and CYP2C19 genotyping were used to guide VCZ dosing in Caucasian patients with IFIs. The two common polymorphisms in Caucasians (CYP2C19*2 and *17), associated with decreased or increased CYP2C19 activity, respectively, were correlated with the daily VCZ dose, pharmacokinetic parameters and concentration-to-dose ratio. In total, 111 trough concentration measurements from 35 genotyped patients were analysed using linear mixed-effect models. The mean VCZ doses required to achieve target concentrations were significantly higher in CYP2C19*17 carriers compared with CYP2C19*1/*1 individuals (P<0.001): 2.57±0.25mg/kg twice daily in CYP2C19*1/*1 patients versus 3.94±0.39mg/kg and 6.75±0.54mg/kg in *1/*17 and *17/*17 patients, respectively. In addition, exposure to VCZ correlated with the CYP2C19*17 variant. Indices of exposure for CYP2C19*2 carriers were in line with the functional effect of this polymorphism compared with CYP2C19*1/*1 individuals, however comparisons of doses required to achieve target concentrations were not statistically different. The CYP2C19*17 allele predicted both VCZ exposure and dose required to achieve effective and non-toxic concentrations. CYP2C19 genotyping appears useful to guide VCZ initial dosing when coupled with TDM and to explain subtherapeutic concentrations frequently observed in clinical practice.
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Rouen, France; INSERM U1096, University of Rouen, School of Medicine, Rouen, France. Electronic address: fabien.lamoureux@chu-rouen.fr.
authors.forename: Fabien
authors.initials: F
authors.lastname: Lamoureux
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Rouen, France; INSERM U1096, University of Rouen, School of Medicine, Rouen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duflot
authors.affiliation: INSERM UMR 850, University of Limoges, CHU Limoges, Limoges, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Woillard
authors.affiliation: INSERM UMR 850, University of Limoges, CHU Limoges, Limoges, France.
authors.forename: David
authors.initials: D
authors.lastname: Metsu
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Rouen, France.
authors.forename: Tony
authors.initials: T
authors.lastname: Pereira
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Rouen, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Compagnon
authors.affiliation: Department of Pneumology, University Hospital, Rouen, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Morisse-Pradier
authors.affiliation: Department of Pneumology, University Hospital, Rouen, France.
authors.forename: Mona
authors.initials: M
authors.lastname: El Kholy
authors.affiliation: Department of Pneumology, University Hospital, Rouen, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Thiberville
authors.affiliation: Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Molecular and Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Jana
authors.initials: J
authors.lastname: Stojanova
authors.affiliation: Department of Pharmacology and Toxicology, University Hospital, Rouen, France; INSERM U1096, University of Rouen, School of Medicine, Rouen, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000188:drug therapy*; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D065819:Voriconazole / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D044465:White People; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: Antifungals; CYP2C19; Drug monitoring; Pharmacogenomics; Voriconazole