title: Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.
abstract: Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences.
authors.affiliation: Genentech Inc., South San Francisco, CA, USA.
authors.forename: Lichuan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Akintunde
authors.initials: A
authors.lastname: Bello
authors.affiliation: Genentech Inc., South San Francisco, CA, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dresser
authors.affiliation: Janssen Research and Development, Spring House, PA, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Heald
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Steven Ferenc
authors.initials: SF
authors.lastname: Komjathy
authors.affiliation: Celgene Corp., Summit, NJ, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: O'Mara
authors.affiliation: Biogen, Inc., Cambridge, MA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Rogge
authors.affiliation: Merck Sharp & Dohme Corp., Lansdale, PA, USA.
authors.forename: S Aubrey
authors.initials: SA
authors.lastname: Stoch
authors.affiliation: Vertex Pharmaceuticals Inc., Boston, MA, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Robertson
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D007654:Ketoconazole
keywords: CYP3A; drug interaction; itraconazole; ketoconazole