title: Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring.
abstract: Posaconazole has become an important part of the antifungal armamentarium in the prophylaxis and salvage treatment of invasive fungal infections (IFIs). Structurally related to itraconazole, posaconazole displays low oral bioavailability due to poor solubility, with significant drug interactions and gastrointestinal disease also contributing to the generally low posaconazole plasma concentrations observed in patients. While therapeutic drug monitoring (TDM) of plasma concentrations is widely accepted for other triazole antifungal agents such as voriconazole, the utility of TDM for posaconazole is controversial due to debate over the relationship between posaconazole exposure in plasma and clinical response to therapy. This review examines the available evidence for a relationship between plasma concentration and clinical efficacy for posaconazole, as well as evaluating the utility of TDM and providing provisional target concentrations for posaconazole therapy. Increasing evidence supports an exposure-response relationship for plasma posaconazole concentrations for prophylaxis and treatment of IFIs; a clear relationship has not been identified between posaconazole concentration and toxicity. Intracellular and intrapulmonary concentrations have been studied for posaconazole but have not been correlated to clinical outcomes. In view of the high mortality and cost associated with the treatment of IFIs, increasing evidence of an exposure-response relationship for posaconazole efficacy in the prevention and treatment of IFIs, and the common finding of low posaconazole concentrations in patients, TDM for posaconazole is likely to be of significant clinical utility. In patients with subtherapeutic posaconazole concentrations, increased dose frequency, administration with high-fat meals, and withdrawal of interacting medications from therapy are useful strategies to improve systemic absorption.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, Australia. mdol7562@uni.sydney.edu.au
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dolton
authors.forename: John E
authors.initials: JE
authors.lastname: Ray
authors.forename: Deborah
authors.initials: D
authors.lastname: Marriott
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D009181:Mycoses / Q000188:drug therapy; D014230:Triazoles
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole