title: Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma.
abstract: The purpose of this article is to report the exposure-response (E-R) relationship of posaconazole oral suspension (POS) for prophylaxis against invasive fungal infections (IFIs), on the basis of the US Food and Drug Administration (FDA) clinical pharmacology review of two randomized, active-controlled clinical studies. Posaconazole average steady state plasma concentrations (C(avg)) ranged from 22 to 3,650 ng/ml after administration of POS 200 mg three times daily (t.i.d.). In a double-blind, randomized clinical trial, the quartile ranges of C(avg) with midpoint values of 289, 736, 1,239, and 2,607 ng/ml had clinical failure rates of 44, 21, 18, and 18%, respectively, indicating an inverse association between C(avg) and clinical failure rate. There were no significant relationships between C(avg) and posaconazole-related major adverse events. Determining posaconazole concentrations in plasma will aid in assessing the need for either POS dose adjustment (e.g., increasing the POS dose) or switching to another systemic antifungal drug, thereby improving the effectiveness of prophylaxis against IFIs.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA. seong.jang@fda.hhs.gov
authors.forename: S H
authors.initials: SH
authors.lastname: Jang
authors.forename: P M
authors.initials: PM
authors.lastname: Colangelo
authors.forename: J V S
authors.initials: JV
authors.lastname: Gobburu
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006086:Graft vs Host Disease / Q000150:complications; D006801:Humans; D009181:Mycoses / Q000517:prevention & control*; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D033581:Stem Cell Transplantation; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D014230:Triazoles; C101425:posaconazole