title: Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity.
abstract: The triazole antifungal voriconazole (VCZ) exhibits broad-spectrum antifungal activity and is the first-line treatment for invasive aspergillosis. Highly variable, non-linear pharmacokinetics, metabolism via the polymorphic drug-metabolising enzyme CYP2C19, and a range of serious adverse events (AEs) including hepatotoxicity and neurotoxicity complicate the clinical utility of VCZ. As interest in optimising VCZ treatment has increased, a growing number of studies have examined the relationships between VCZ exposure and efficacy in the treatment and prevention of invasive fungal infections, as well as associations with VCZ-related AEs. This review provides a critical analysis of VCZ pharmacokinetics and exposure-response (E-R) relationships, assessing the links between VCZ exposure, efficacy and toxicity. Low VCZ exposure has frequently been associated with a higher incidence of treatment failure; fewer studies have addressed E-R relationships with prophylactic VCZ. VCZ-related neurotoxicity appears common at high VCZ concentrations and can be minimised by maintaining concentrations below the recommended upper concentration thresholds; hepatotoxicity appears to be associated with increased VCZ exposure but is also prevalent at low concentrations. Further research should aim to inform and optimise the narrow therapeutic range of VCZ as well as develop interventions to individualise VCZ dosing to achieve maximal efficacy with minimal toxicity.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dolton
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia; Centre for Education and Research on Ageing, Concord Repatriation General Hospital, Sydney, NSW, Australia. Electronic address: andrew.mclachlan@sydney.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D001228:Aspergillosis / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D006801:Humans; D017211:Treatment Failure; D065819:Voriconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D065819:Voriconazole
keywords: Antifungal; Azoles; Exposure–response; Pharmacodynamics; Pharmacokinetics; Voriconazole