title: The pharmacokinetics and safety of idelalisib in subjects with moderate or severe hepatic impairment.
abstract: Idelalisib, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117, an inactive metabolite, and is metabolized to a lesser extent by cytochrome P450 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In a mass balance study, the orally administered idelalisib dose was recovered mainly in feces (∼78%). This study evaluated the pharmacokinetics and safety of a single 150-mg dose of idelalisib in subjects with moderate or severe hepatic impairment and in age-, sex-, and weight-matched, healthy controls. The idelalisib maximum observed plasma concentration was generally comparable in subjects with moderate or severe hepatic impairment versus healthy controls, whereas the mean area under the curve was higher (58% to 59%). GS-563117 exposures were lower in impaired versus healthy control subjects, likely because of lower formation in the setting of liver impairment. Exploratory analyses indicated no relevant relationships between idelalisib or GS-563117 plasma exposures and Child-Pugh-Turcotte scores. Single oral doses of idelalisib 150 mg were well tolerated, with most treatment-emergent adverse events (AEs) and laboratory abnormalities being grades 1 or 2 in severity. As such, no dose adjustment was required when initiating idelalisib treatment in patients with mild or moderate hepatic impairment, although close monitoring for potential AEs is recommended.
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: Grace
authors.initials: G
authors.lastname: Hisoire
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, USA.
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics*; D052999:Quinazolinones / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib
keywords: PI3Kδ; hepatic impairment; idelalisib; pharmacokinetics; safety