Background and Objectives
Controversy exists regarding dose adjustment in patients treated with voriconazole due to the severity of the infections for which it is prescribed. The Dutch Pharmacogenetics Working Group (DPWG) recommends a 50% dose increase or decrease for cytochrome P450 (CYP) 2C19 ultrarapid (UM) or poor (PM) metabolizers, respectively. In contrast, for the previous phenotypes, the Clinical Pharmacogenetics Implementation Consortium (CPIC) voriconazole guideline only recommends a change of treatment. Based on observed data from single-dose bioequivalence studies and steady-state observed concentrations, we aimed to investigate voriconazole dose adjustments by means of physiologically based pharmacokinetic (PBPK) modeling.
PBPK modeling was used to optimize voriconazole single-dose models for each CYP2C19 phenotype, which were extrapolated to steady state and evaluated for concordance with the therapeutic range of voriconazole. Based on optimized models, dose adjustments were evaluated for better adjustment to the therapeutic range.
Our models suggest that the standard dose may only be appropriate for normal metabolizers (NM), although they would benefit from a 50–100% loading dose increase. Intermediate metabolizers (IMs) and PMs required a daily dose reduction of 50 and 75%, respectively. Rapid metabolizers (RMs) and UMs required a daily dose increase of 100% and 300%, respectively.
The prescription of voriconazole in clinical practice should be personalized according to the CYP2C19 phenotype, followed by therapeutic drug monitoring of plasma concentrations to guide dose adjustment.
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Dora Koller is financed by the H2020 Marie Skłodowska Curie Innovative Training Network 721236 grant. Irene García García is financed by Instituto de Salud Carlos III by the Rio Hortega grant. Marcos Navares-Gomez is co-financed by Consejería de Educación, Juventud y Deporte from Comunidad de Madrid and Fondo Social Europeo. No funds were received for the current research.
Conflict of Interest
Francisco Abad-Santos and Dolores Ochoa have been consultants or investigators in clinical trials sponsored by Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. Pablo Zubiaur, Lisa A. Kneller, Gina Mejía, Miriam Saiz-Rodríguez, Alberto M. Borobia, Dora Koller, Irene García García, Marcos Navares-Gómez, and Georg Hempel declare no conflicts of interest.
Study protocols were approved by an independent Research Ethics Committee. In addition, the protocols were duly authorized by the Spanish Medicines Agency (AEMPS) and were carried out under the guidelines of Good Clinical Practices, complying with current Spanish legislation on clinical research in humans and with the Declaration of Helsinki. EUDRA-CT numbers: 2012–004029-26, 2014–001964-36, and 2014–005342-22.
Consent for Participation
All subjects provided informed consent to participate in the present research.
Availability of Data and Material
Data are available from the corresponding author upon reasonable request.
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Zubiaur, P., Kneller, L.A., Ochoa, D. et al. Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling. Clin Pharmacokinet (2020). https://doi.org/10.1007/s40262-020-00941-8