title: 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 (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.
authors.affiliation: Institute of Clinical Pharmacology, University Teaching Hospital of Udine, Udine, Italy.|Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Cojutti
authors.affiliation: Division of Haematology, University Teaching Hospital of Udine, Udine, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Candoni
authors.affiliation: Department of Medical and Surgical Sciences, Section of Haematology, University of Modena and Reggio Emilia, University Teaching Hospital of Modena, Modena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Forghieri
authors.affiliation: Department of Medical and Biological Sciences, Section of Statistics, University of Udine, Udine, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Isola
authors.affiliation: Division of Haematology, University Teaching Hospital of Udine, Udine, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Zannier
authors.affiliation: Department of Medical and Surgical Sciences, Section of Haematology, University of Modena and Reggio Emilia, University Teaching Hospital of Modena, Modena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bigliardi
authors.affiliation: Department of Medical and Surgical Sciences, Section of Haematology, University of Modena and Reggio Emilia, University Teaching Hospital of Modena, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Division of Haematology, University Teaching Hospital of Udine, Udine, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Fanin
authors.affiliation: Institute of Clinical Pharmacology, University Teaching Hospital of Udine, Udine, Italy.|Department of Experimental and Clinical Medical Sciences, University of Udine, Udine, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Pea
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D065693:Cytochrome P-450 Enzyme Inducers / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D016903:Drug Monitoring / Q000706:statistics & numerical data; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D000072742:Invasive Fungal Infections / Q000188:drug therapy*; D007558:Italy; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D016896:Treatment Outcome; D065819:Voriconazole / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D065693:Cytochrome P-450 Enzyme Inducers; D065607:Cytochrome P-450 Enzyme Inhibitors; D065819:Voriconazole