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.

Voriconazole is an antifungal metabolised by CYP2C19 enzyme, which can be inhibited by proton‐pump inhibitors (PPIs). A prospective observational study was carried out to determine the influence of PPIs on voriconazole pharmacokinetic. The 78 patients included were divided into 4 groups: omeprazole (n = 32), pantoprazole (n = 25), esomeprazole (n = 3) and no PPI (n = 18). Patients with no PPI had no significant difference in plasma voriconazole concentration when compared with those with PPI (2.63 ± 2.13 μg/mL [95% confidence interval {CI} 1.57–3.69] vs 2.11 ± 1.73 μg/mL [95%CI 1.67–2.55], P > .05). However, voriconazole plasma concentration was significantly lower in patients treated with pantoprazole vs those treated with omeprazole (1.44 ± 1.22 μg/mL [95%CI 0.94–1.94) vs 2.67 ± 1.88 μg/mL [95%CI 2.02–3.32], P = .013) suggesting a greater CYP2C19 enzyme inhibitory effect of omeprazole. This study demonstrates the greater CYP inhibition capacity of omeprazole and should be helpful for the choice of PPIs for patients treated with voriconazole.

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This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.