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. 2019 Mar 27;63(4):e02353-18.
doi: 10.1128/AAC.02353-18. Print 2019 Apr.

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study

William Hope  1   2 , Gary Johnstone  3 , Silvia Cicconi  3 , Timothy Felton  4   5 , Joanne Goodwin  6 , Sarah Whalley  6 , Anahi Santoyo-Castelazo  6 , Virginia Ramos-Martin  6 , Jodi Lestner  6 , Leah Credidio  2 , Aaron Dane  6   7 , Daniel F Carr  8 , Munir Pirmohamed  2   8 , Rahim Salim  2 , Michael Neely  9
Affiliations

Software for Dosage Individualization of Voriconazole: a Prospective Clinical Study

William Hope et al. Antimicrob Agents Chemother. .

Abstract

Voriconazole is a first-line antifungal agent. Therapeutic drug monitoring is a standard of care. The best way to adjust dosages to achieve desired drug exposure endpoints is unclear due to nonlinear and variable pharmacokinetics. Previously described software was used to prospectively adjust voriconazole dosages. The CYP2C19, CYP3A4, and CYP3A5 genotypes were determined. The primary endpoint was the proportion of patients with a Cmin at 120 h in the range 1 to 3 mg/liter using software to adjust voriconazole dosages. A total of 19 patients were enrolled, and 14 were evaluable. Of these, 12/14 (85.7%; 95% confidence interval = 57.2 to 98.2%) had a Cmin at 120 h posttreatment initiation of 1 to 3 mg/liter, which was higher than the a priori expected proportion of 33%. There was no association of CYP genotype-derived metabolizer phenotype with voriconazole AUC. Software can be used to adjust the dosages of voriconazole to achieve drug exposures that are safe and effective. (The clinical trial discussed in this paper has been registered in the European Clinical Trials Database under EudraCT no. 2013-0025878-34 and in the ISRCTN registry under no. ISRCTN83902726.).

Keywords: antifungal agents; antifungal therapy; mathematical modeling; pharmacokinetics; population pharmacokinetics; software; voriconazole.

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Figures

FIG 1
FIG 1
Schema of the study design. The blue dots refer to sampling times for the PK for the first and second rounds of dosage individualization. The yellow triangles represent the sampling strategy to define the primary endpoint. Ind 1 and Ind 2 are the dosage predictions from BestDose in the first and second rounds of dosage individualization, respectively. (Illustration courtesy of Patrick Lane.)
FIG 2
FIG 2
Spaghetti plot showing the PK data for the study patients. The broken red lines indicate the target concentration range of 1 to 3 mg/liter. A total of 12/14 patients achieved a Cmin within the range 1 to 3 mg at 120 h.
FIG 3
FIG 3
Relationship between AUC0–24 in the initial 24 h of voriconazole therapy and genotype. The medians, interquartile ranges (IQR), and 5th and 95th percentiles are shown in each box plot.
See this image and copyright information in PMC

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