title: Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing.
abstract: OBJECTIVE
  Voriconazole exhibits highly variable, non-linear pharmacokinetics and is associated with a narrow therapeutic range. This study aimed to investigate the population pharmacokinetics of voriconazole in adults, including the effect of CYP2C19 genotype and drug-drug interactions.
  
  
  METHODS
  Non-linear mixed effects modelling (NONMEM) was undertaken of six voriconazole studies in healthy volunteers and patients. Dosing simulations to examine influential covariate effects and voriconazole target attainment (2-5 mg/L) stratified by CYP2C19 phenotype were performed.
  
  
  RESULTS
  We analysed 3352 voriconazole concentration measurements from 240 participants. A two-compartment pharmacokinetic model with first-order oral absorption with lag time and Michaelis-Menten elimination best described voriconazole pharmacokinetics. Participants with one or more CYP2C19 loss-of-function (LoF) alleles had a 41.2% lower Vmax for voriconazole. Co-administration of phenytoin or rifampicin, St John's wort or glucocorticoids significantly increased voriconazole elimination. Among patients receiving 200 mg of voriconazole twice daily, predicted trough concentrations on day 7 were <2 mg/L for oral and intravenous regimens for 72% and 63% of patients without CYP2C19 LoF alleles, respectively, with 49% and 35% below this threshold with 300 mg twice daily dosing. Conversely, these regimens resulted in 29%, 39%, 57% and 77% of patients with CYP2C19 LoF alleles with voriconazole trough concentrations ≥5 mg/L.
  
  
  CONCLUSIONS
  Current dosing regimens for voriconazole result in subtherapeutic exposure in many patients without CYP2C19 LoF alleles, suggesting the need for higher doses, whereas these regimens result in supratherapeutic exposure in a high proportion of patients with reduced CYP2C19 activity. These findings support the essential role of therapeutic drug monitoring in ensuring efficacious and safe voriconazole exposure.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Camperdown, Australia Centre For Education and Research on Ageing, Concord Repatriation General Hospital, Concord, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dolton
authors.affiliation: Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.affiliation: Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Clinical Pharmacology and Toxicology, SydPath, St Vincent's Hospital, Darlinghurst, Australia.
authors.forename: John E
authors.initials: JE
authors.lastname: Ray
authors.affiliation: Faculty of Pharmacy, University of Sydney, Camperdown, Australia Centre For Education and Research on Ageing, Concord Repatriation General Hospital, Concord, Australia andrew.mclachlan@sydney.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D016903:Drug Monitoring; D005838:Genotype; D006801:Humans; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D010641:Phenotype; D011159:Population Surveillance; D015203:Reproducibility of Results; D065819:Voriconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
keywords: CYP2C19; antifungals; azoles