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Clinical drug interaction profile of idelalisib in healthy subjects
Author(s) -
Jin Feng,
Robeson Michelle,
Zhou Huafeng,
Moyer Candra,
Wilbert Sibylle,
Murray Bernard,
Ramanathan Srini
Publication year - 2015
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.495
Subject(s) - idelalisib , drug drug interaction , drug , medicine , pharmacology , ibrutinib , chronic lymphocytic leukemia , leukemia
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 [C max ] and area under the plasma concentration–time curve from time 0 extrapolated to infinity [AUC inf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS‐563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, C max and AUC inf , respectively) and GS‐563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.