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 (Cmin ). Voriconazole Cmin 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 Cmin . 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 Cmin value (n = 199) was 2.4 mg/L with a wide range of distribution (<0.2-13.5 mg/L). Median (IQR) normalized voriconazole Cmin 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 Cmin >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 Cmin 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.
Highlights
Voriconazole plasma exposure greatly varies among haematological patients
The comparative analysis showed that normalized Cmin values were significantly lower in patients receiving oral pantoprazole at 20 mg/day than in patients receiving either IV omeprazole at 80 mg/day (p < 0.015) or IV pantoprazole at 80 mg/day (p = 0.03). This retrospective study is the first to directly compare in real life the influence that the absence or presence of cotreatments with cytochrome P450 (CYP) inhibitors and/or with CYP inhibitors plus CYP inducers may have on the maintenance of appropriate exposure to voriconazole in high-risk haematological patients
The findings suggest that dose-normalized voriconazole Cmin may be significantly influenced by various interacting drugs, but to a very different extent in relation to the type and to the administered dose of the drug
Summary
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 (Cmin). It should not be overlooked that voriconazole is a highly lipophilic azole antifungal which is extensively metabolized by several isoforms of the cytochrome P450 (CYP), mainly by CYP2C19 and to a lesser extent by CYP2C9 and CYP3A4 [5] This means that voriconazole exposure may greatly vary among different individuals even when the recommended dose per kg of body-weight is administered. Factors responsible for this intra- and interindividual pharmacokinetic variability may be related either to genetic polymorphisms of CYP [6] or to drug–drug pharmacokinetic interactions with CYP inhibitors and/or with CYP inducers [7,8]. This may maximize the likelihood of optimal treatment while avoiding the risk of underexposure with treatment failure or of overexposure with drug-related toxicity [10,11,12]
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