title: Clinical drug interaction profile of idelalisib in healthy subjects.
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 plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ], respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.affiliation: Gilead Sciences, Inc., Seattle, WA, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Robeson
authors.affiliation: Gilead Sciences, Inc., Seattle, WA, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Candra
authors.initials: C
authors.lastname: Moyer
authors.affiliation: Gilead Sciences, Inc., Seattle, WA, USA.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Wilbert
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Murray
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D052999:Quinazolinones / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012293:Rifampin / Q000494:pharmacology; D000068718:Rosuvastatin Calcium / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D004077:Digoxin; D000068718:Rosuvastatin Calcium; D008874:Midazolam; D012293:Rifampin; C552946:idelalisib
keywords: PI3Kδ; drug interaction; idelalisib; pharmacokinetics; safety