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J Antimicrob Chemother. 2014 Jun;69(6):1633-41. doi: 10.1093/jac/dku031. Epub 2014 Feb 18.

Understanding variability with voriconazole using a population pharmacokinetic approach: implications for optimal dosing.

Author information

1
Faculty of Pharmacy, University of Sydney, Camperdown, Australia Centre For Education and Research on Ageing, Concord Repatriation General Hospital, Concord, Australia.
2
Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Heidelberg, Germany.
3
Clinical Pharmacology and Toxicology, SydPath, St Vincent's Hospital, Darlinghurst, Australia.
4
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.

Abstract

OBJECTIVES:

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.

KEYWORDS:

CYP2C19; antifungals; azoles

PMID:
24554646
DOI:
10.1093/jac/dku031
[Indexed for MEDLINE]

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