title: Itraconazole and clarithromycin as ketoconazole alternatives for clinical CYP3A inhibition studies.
abstract: High-dose ketoconazole (400 mg q.d. for ≥5 days) has been the gold-standard strong cytochrome P450 3A (CYP3A) inhibitor in drug development drug-drug interaction (DDI) studies. In 2013, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) advised against using this ketoconazole regimen following review of clinical safety reports. We systematically evaluated 19 strong CYP3A inhibitors from regulatory guidances and a literature database to identify itraconazole (200 mg b.i.d. on day 1, q.d. on days 2-6) and clarithromycin (500 mg b.i.d. for 7 days) as acceptable ketoconazole alternatives.
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Ke
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Higgins
authors.affiliation: Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Hall
mesh_terms: D017291:Clarithromycin / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D016208:Databases, Factual; D015195:Drug Design; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005060:Europe; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000494:pharmacology*; D007654:Ketoconazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D017964:Itraconazole; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D017291:Clarithromycin; D007654:Ketoconazole