Impact of CYP2C19 Genotype and Drug Interactions on Voriconazole Plasma Concentrations: A Spain Pharmacogenetic‐Pharmacokinetic Prospective Multicenter Study

Abstract

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.

Interactive Effects of Glucocorticoids and Cytochrome P450 Polymorphisms on the Plasma Trough Concentrations of Voriconazole

“…Although VRC could be metabolized by various CYP450 enzymes induced by corticosteroid ( Li et al, 2017 ), the specific interference effect of glucocorticoids on the concentration and pharmacokinetics of VRC is still controversial ( Dolton et al, 2012 ; Gautier-Veyret et al, 2015 ; Li et al, 2017 ; Imataki et al, 2018 ; Blanco-Dorado et al, 2020 ). Hence, the effects of glucocorticoid type and dosage on VRC remains to be further studied.…”

“…However, the results of different researches are inconsistent. It is a hot spot of controversy whether concomitant with glucocorticoids affects VRC C min and whether different glucocorticoids (ie., dexamethasone, prednisone, prednisolone, and methylprednisolone) have same effects on VRC concentrations ( Eiden et al, 2010 ; Dolton et al, 2012 ; Gautier-Veyret et al, 2015 ; Cojutti et al, 2016 ; Li et al, 2017 ; Blanco-Dorado et al, 2020 ), and the mechanism of this interaction is still unclear. In general, glucocorticoids are strong inducers of CYP2C9, CYP2C11, CYP2C19, CYP3A4, CYP3A5, and CYP3A7 ( Iber et al, 1997 ; Chen et al, 2003 ; Zhou et al, 2009 ; Dvorak and Pavek, 2010 ; Matsunaga et al, 2012 ; Matoulkova et al, 2014 ), which leads to a C min decrease of drugs that are metabolized primarily by these CYP450s.…”

Evaluación de las concentraciones plasmáticas de voriconazol en práctica clínica

“…La ficha técnica de voriconazol hace referencia a fármacos en los que su administración concomitante está contraindicada (1) Además, en base a la experiencia clínica, se han observado otros fármacos cuyo impacto en las C min de voriconazol podría ser significativo. Por ejemplo, varios trabajos retrospectivos (14,15) han asociado el uso concomitante con corticoides con C min de voriconazol inferiores. Una hipótesis es que los glucocorticoides inducen el CYP2C19 y posiblemente, también de CYP3A4, provocando un incremento del metabolismo de voriconazol (14) .…”

Impact of cytochrome P450 2C19 polymorphisms on the clinical efficacy and safety of voriconazole: an update systematic review and meta-analysis

“…Most of these studies were carried out in Asia (China, Korea). Voriconazole was used for treatment in most studies, and for prophylaxis in three studies 23,24,26 , as well as for treatment or prophylaxis in three studies 18,22,25 . Most studies followed the standard dosing of 6mg/kg (IV)/400mg (Oral) twice daily on day 1 for load and 4mg/kg (IV)/200mg (Oral) twice daily for maintenance.…”

“…Thirteen studies analyzed the association of CYP2C19 phenotype with the safety outcome of overall adverse events 14,21,[25][26][27][28][29][30][31][32][33][34][35] and meta-analysis results were shown in Table 4. In total, PMs were at increased risk of overall adverse events in comparison with NMs (RR:2.18, 95% CI: 1.35˜3.53,I 2 =37%, p=0.001) 21, 25, 26, 28, 30, 32-35 and IMs (RR: 1.80, 95% CI: 1.23˜2.64,I 2 =0%, p=0.003) 21,25,26,[28][29][30][31][32][33][34][35] . There were no significant differences in other comparisons.…”