Clinical drug interaction profile of idelalisib in healthy subjects

Journal of Clinical Pharmacology
Feng JinSrini Ramanathan

Abstract

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration [Cmax ] and area under the pl...Continue Reading

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Citations

Jan 29, 2016·Expert Opinion on Pharmacotherapy·Solomon Graf, Ajay Gopal
Aug 6, 2015·Clinical Pharmacokinetics·Srinivasan RamanathanBrian P Kearney
Mar 17, 2016·Journal of Medicinal Chemistry·Leena PatelGary Phillips
Jun 15, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert S Foti, Deepak K Dalvie
Aug 19, 2018·Pharmacotherapy·Laura A TangTim J Peterson
Aug 7, 2019·Clinical Pharmacokinetics·Nikki BlosserDouglas Stewart
Nov 2, 2019·Clinical and Translational Science·Mariam A AhmedDaria Stypinski
Jun 1, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Christine Beedham
Jul 1, 2017·Radiation Oncology·Thomas GrycBarbara Schuster
Jul 31, 2020·Expert Opinion on Drug Metabolism & Toxicology·Takeshi HirotaIchiro Ieiri
Sep 25, 2019·Drug Metabolism Reviews·Narges CheshmazarMaryam Hamzeh-Mivehroud
Mar 12, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Alexey V DanilovChristopher D Fegan
Apr 4, 2021·International Journal of Molecular Sciences·María N BarrachinaÁngel García
Jun 14, 2018·Chemical Research in Toxicology·Junjie ZhuXiaochao Ma

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