Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450(CYP) Inhibitors and/or with CYP Inhibitors plus CYP Inducers

Abstract

Voriconazole plasma exposure greatly varies among haematological patients. The purpose of this study was to identify the magnitude of influence of comedications with CYP inhibitors and/or with CYP inhibitors plus CYP inducers on voriconazole trough level (C min ). Voriconazole C min was retrospectively assessed among haematological patients who underwent therapeutic drug monitoring (TDM). Univariate and multivariate linear mixed-effect regression analyses were performed to identify the independent predictors of normalized C min . Of the 83 included patients, 35 had comedications with CYP inhibitors (omeprazole or pantoprazole) and 21 with CYP inhibitors (omeprazole or pantoprazole) plus CYP inducers (methylprednisolone, dexamethasone, phenobarbital, rifampin or carbamazepine). Median C min value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2-13.5 mg/L). Median (IQR) normalized voriconazole C min value was significantly higher in the presence of CYP inhibitors (4.20 mg/L, 3.23-5.51 mg/L) than either in the absence of interacting cotreatments (2.55 mg/L, 1.54-3.47 mg/L) or in the presence of CYP inhibitors plus CYP inducers (2.16 mg/L, 1.19-3.09 mg/L). The presence of CYP inhibitors was highly significantly associated with C min >5.5 mg/L (OR: 23.22, 95% CI: 3.01-179.09, p = 0.003). No significant association emerged when CYP inhibitors were coadministered with CYP inducers (OR: 3.53, 95% CI: 0.36-34.95, p = 0.280). The amount of expected C min increase was significantly influenced by both the type and the dose of the administered proton pump inhibitor. The study highlights that the benefit from TDM of voriconazole may be maximal in those patients who are cotreated with CYP inhibitors and/or with CYP inhibitors plus CYP inducers, especially when receiving proton pump inhibitors (PPIs) at very high dosages intravenously.

The influence of combination use of CYP450 inducers on the pharmacokinetics of voriconazole: a systematic review

“…Three studies (Eiden et al, Dolton et al, Naito et al) 28,29,31 reported that glucocorticoids slightly elevated the metabolism of voriconazole, although it did not affect the plasma exposure of voriconazole. Two studies (Dolton et al, Cojutti et al) 27,34 found that co-administration of voriconazole with glucocorticoids led to a significant decrease in normalized voriconazole C min (P < 0Á001), and co-administration of methylprednisolone and dexamethasone had a greater effect on voriconazole concentration than did prednisone or prednisolone co-administration (Table 3).…”

Voriconazole hepatotoxicity as a result of steroid withdrawal in a patient with allergic bronchopulmonary aspergillosis

“…An in vitro study has identified glucocorticoid receptor binding sites in the promoter region of the CYP2C19 gene and demonstrated up‐regulation of CYP2C19, supporting an inductive effect of glucocorticoids on CYP2C19 . There are limited data regarding the interaction between voriconazole and corticosteroids in clinical practice . Dolton et al found that concomitant dexamethasone use was associated with a 3.75‐fold decrease in voriconazole concentrations .…”

Impact of the CYP2C19 genotype on voriconazole exposure in adults with invasive fungal infections

“…There is a large body of evidence demonstrating that therapeutic success with voriconazole is contingent on achieving a therapeutic trough plasma concentration at steady state [7–9], and response rates approach 100% when trough concentrations of at least 2 mg/L are attained early in the course of therapy [3,10,11]. However, the recommended weight-based voriconazole dosing for the treatment IFIs, which consists of a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours, is associated with a wide inter-individual variability in voriconazole exposure [7,12], with reported troughs ranging from 0.2 mg/L to 13.5 mg/L [12,13]. …”