title: Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring.
abstract: Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of <1.7 mg/liter were associated with a significantly greater incidence of treatment failure (19/74 patients [26%]) than concentrations of ≥1.7 mg/liter (6/89 patients [7%]) (P < 0.01). Neurotoxic adverse events (visual and auditory hallucinations) occurred more frequently at voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P < 0.01). Multiple regression analysis of voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole.
authors: Faculty of Pharmacy, University of Sydney, Camperdown, Australia.
authors: Michael J
authors: MJ
authors: Dolton
authors: John E
authors: JE
authors: Ray
authors: Sharon C-A
authors: SC
authors: Chen
authors: Kingsley
authors: K
authors: Ng
authors: Lisa G
authors: LG
authors: Pont
authors: Andrew J
authors: AJ
authors: McLachlan
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001315:Australia; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D003904:Mitosporic Fungi / Q000187:drug effects* / Q000254:growth & development; D009181:Mycoses / Q000188:drug therapy* / Q000382:microbiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D010672:Phenytoin / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D005938:Glucocorticoids; D019384:Nucleic Acid Synthesis Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D061567:Voltage-Gated Sodium Channel Blockers; D010672:Phenytoin; D065819:Voriconazole; D012293:Rifampin