Sara Blanco-Dorado1,2,3, Olalla Maroñas4,5, Ana Latorre-Pellicer4, María Teresa Rodríguez Jato1, Ana López-Vizcaíno6, Aurea Gómez Márquez7, Belén Bardán García8, Dolores Belles Medall9, Gema Barbeito Castiñeiras10, María Luisa Pérez Del Molino Bernal10, Manuel Campos-Toimil3, Francisco Otero Espinar3, Andrés Blanco Hortas11, Goretti Durán Piñeiro2, Irene Zarra Ferro1,2, Ángel Carracedo4,5, María Jesús Lamas2, Anxo Fernández-Ferreiro1,2,3. 1. Pharmacy Department, University Clinical Hospital Santiago de Compostela (CHUS), Santiago de Compostela, Spain. 2. Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital, Santiago de Compostela, Spain. 3. Department of Pharmacology, Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Santiago de Compostela (USC), Santiago de Compostela, Spain. 4. Genomic Medicine Group, Centro Nacional de Genotipado (CEGEN-PRB3), CIBERER, CIMUS, University of Santiago de Compostela (USC), Santiago de Compostela, Spain. 5. Galician Foundation of Genomic Medicine, Health Research Institute of Santiago de Compostela (IDIS), SERGAS, Santiago de Compostela, Spain. 6. Pharmacy Department, University Hospital Lucus Augusti (HULA), Lugo, Spain. 7. Pharmacy Department, University Hospital Ourense (CHUO), Ourense, Spain. 8. Pharmacy Department, University Hospital Ferrol (CHUF), A Coruña, Spain. 9. Pharmacy Department, General University Hospital Castellón (GVA), Castellon, Spain. 10. Microbiology Department, University Clinical Hospital Santiago de Compostela (CHUS), Santiago de Compostela, Spain. 11. Epidemiology Unit, Fundación Instituto de Investigación Sanitaria de Santiago de Compostela (FIDIS), University Hospital Lucus Augusti (HULA), Lugo, Spain.
Abstract
BACKGROUND: Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.
BACKGROUND:Voriconazole, a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by cytochrome P450 (CYP) 2C19. A significant portion of patients fail to achieve therapeutic voriconazole trough concentrations, with a consequently increased risk of therapeutic failure. OBJECTIVE: To show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions. METHODS: Adults receiving voriconazole for antifungal treatment or prophylaxis were included in a multicenter prospective study conducted in Spain. The prevalence of subtherapeutic voriconazole troughs was analyzed in the rapid metabolizer and ultra-rapid metabolizer patients (RMs and UMs, respectively), and compared with the rest of the patients. The relationship between voriconazole concentration, CYP2C19 phenotype, adverse events (AEs), and drug-drug interactions was also assessed. RESULTS: In this study 78 patients were included with a wide variability in voriconazole plasma levels with only 44.8% of patients attaining trough concentrations within the therapeutic range of 1 and 5.5 µg/ml. The allele frequency of *17 variant was found to be 29.5%. Compared with patients with other phenotypes, RMs and UMs had a lower voriconazole plasma concentration (RM/UM: 1.85 ± 0.24 µg/ml vs other phenotypes: 2.36 ± 0.26 µg/ml). Adverse events were more common in patients with higher voriconazole concentrations (p<0.05). No association between voriconazole trough concentration and other factors (age, weight, route of administration, and concomitant administration of enzyme inducer, enzyme inhibitor, glucocorticoids, or proton pump inhibitors) was found. CONCLUSION: These results suggest the potential clinical utility of using CYP2C19 genotype-guided voriconazole dosing to achieve concentrations in the therapeutic range in the early course of therapy. Larger studies are needed to confirm the impact of pharmacogenetics on voriconazole pharmacokinetics.