Premium
Variability of Voriconazole Trough Levels in Haematological Patients: Influence of Comedications with cytochrome P450( CYP ) Inhibitors and/or with CYP Inhibitors plus CYP Inducers
Author(s) -
Cojutti Piergiorgio,
Candoni Anna,
Forghieri Fabio,
Isola Miriam,
Zannier Maria Elena,
Bigliardi Sara,
Luppi Mario,
Fanin Renato,
Pea Federico
Publication year - 2016
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12530
Subject(s) - cmin , pharmacology , voriconazole , cyp3a , cyp2c19 , pharmacokinetics , drug interaction , therapeutic drug monitoring , cyp2c9 , medicine , cytochrome p450 , cmax , chemistry , metabolism , antifungal , dermatology
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 ( PPI s) at very high dosages intravenously.