• Sara Blanco-Dorado, Olalla Maroñas, Ana Latorre-Pellicer, María Teresa Rodríguez Jato, Ana López-Vizcaíno, Aurea Gómez Márquez, Belén Bardán García, Dolores Belles Medall, Gema Barbeito Castiñeiras, María Luisa Pérez Del Molino Bernal, Manuel Campos-Toimil, Francisco Otero Espinar, Andrés Blanco Hortas, Goretti Durán Piñeiro, Irene Zarra Ferro, Ángel Carracedo, María Jesús Lamas, and Anxo Fernández-Ferreiro.
• Pharmacy Department, University Clinical Hospital Santiago de Compostela (CHUS), Santiago de Compostela, Spain.
• Pharmacotherapy. 2020 Jan 1; 40 (1): 17-25.

BackgroundVoriconazole, 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.ObjectiveTo show the association between subtherapeutic voriconazole concentrations and factors affecting voriconazole pharmacokinetics: CYP2C19 genotype and drug-drug interactions.MethodsAdults 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.ResultsIn 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.ConclusionThese 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.© 2019 Pharmacotherapy Publications, Inc.

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