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-Santos6,7,8,9. 1. Clinical Pharmacology Department, La Princesa University Hospital, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), C/Diego de León, 62, 28006, Madrid, Spain. 2. UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain. 3. Institute of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany. 4. Research Unit, Fundación Burgos Por La Investigación de La Salud, Hospital Universitario de Burgos, Burgos, Spain. 5. School of Medicine, Clinical Pharmacology Department, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain. 6. Clinical Pharmacology Department, La Princesa University Hospital, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria La Princesa (IP), Universidad Autónoma de Madrid (UAM), C/Diego de León, 62, 28006, Madrid, Spain. francisco.abad@salud.madrid.org. 7. UICEC Hospital Universitario de La Princesa, Plataforma SCReN (Spanish Clinical Research Network), Instituto de Investigación Sanitaria La Princesa (IP), Madrid, Spain. francisco.abad@salud.madrid.org. 8. School of Medicine, Clinical Pharmacology Department, La Paz University Hospital, Universidad Autónoma de Madrid, Madrid, Spain. francisco.abad@salud.madrid.org. 9. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. francisco.abad@salud.madrid.org.
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.
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.