Evaluation of Voriconazole CYP2C19 Phenotype-Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling
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ORIGINAL RESEARCH ARTICLE
Evaluation of Voriconazole CYP2C19 Phenotype‑Guided Dose Adjustments by Physiologically Based Pharmacokinetic Modeling Pablo Zubiaur1,2 · Lisa A. Kneller3 · Dolores Ochoa1,2 · Gina Mejía1,2 · Miriam Saiz‑Rodríguez1,4 · Alberto M. Borobia5 · Dora Koller1 · Irene García García5 · Marcos Navares‑Gómez1 · Georg Hempel3 · Francisco Abad‑Santos1,2,5,6
© Springer Nature Switzerland AG 2020
Abstract 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. Methods 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. Results 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. Conclusion 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.
1 Introduction Voriconazole is a triazole, broad-spectrum antifungal drug used for the treatment of several serious infections in adults and children aged ≥ 2 years, namely invasive aspergillosis, candidemia, fluconazole-resistant Candida spp. infections or Scedosporium spp. and Fusarium spp. infections [1]. Voriconazole is rapidly absorbed [time to reach maximum concentration (Tmax) NM > RM > UM). Figure 1 (electronic supplementary Table 1) shows voriconazole concentrations at 0–24 h according to the CYP2C19 phenotype. Regarding the demographics of volunteers from the work of Dodds Ashley et al. [16], a total of 20 healthy volunteers were enrolled; half were men and the other half were women, with a mean age of 27.6 years and a body mass index (BMI) range of 19–28 kg/m2. The reason behind selecting the latter work for steady-state optimization was the similarities in demographic parameters between their population and our population. Concentrations between
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