Impact of CYP2C19 genotype and drug interactions on voriconazole plasma concentrations: a spain pharmacogenetic-pharmacokinetic prospective multicenter study.
Pharmacotherapy. 2019 Nov 29;:
Authors: Blanco Dorado S, Maroñas O, Latorre-Pellicer A, Rodríguez Jato T, López-Vizcaíno A, Gómez Márquez A, Bardán García B, Belles Medall D, Barbeito Castiñeiras G, Pérez Del Molino Bernal ML, Campos-Toimil M, Otero Espinar F, Blanco Hortas A, Durán Piñeiro G, Zarra Ferro I, Carracedo Á, Lamas MJ, Fernández-Ferreiro A
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 were 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 versus 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.
PMID: 31782536 [PubMed – as supplied by publisher]