The Pharmacokinetics and Safety Of Idelalisib In Subjects With Moderate Or Severe Hepatic Impairment

Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110s catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on mass balance study of IDELA, the majority of the radioactive dose administered in healthy subjects was recovered in feces (∼78%).  The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with moderate or severe hepatic impairment following administration of a single oral dose of IDELA.

Eligible subjects were enrolled into 2 cohorts that included subjects with moderate or severe hepatic dysfunction as categorized by the ChildPugh-Turcotte (CPT) classification system and healthy controls matched for age, gender, and body mass index. Each subject received a single oral dose of IDELA at 150 mg under fed condition. Blood samples for IDELA and GS-563117 were collected over 6 days post-dose and were measured using a validated LC/MS/MS method. The ratio and 90% confidence interval of the least squares geometric means of PK exposure parameters in the hepatic impairment group(s) versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study.

A total of 32 subjects were enrolled in the study. The majority of subjects were white (87.5%) males (71.9%) and median age was 52 years. Study treatments were generally well tolerated. The majority of the treatment-emergent AEs (TEAE) were assessed as Grade 1 in severity. The only TEAE reported in more than 1 subject was headache (5 subjects overall; 2 subjects with moderate hepatic impairment and 3 healthy subjects). Most treatmentemergent laboratory abnormalities were Grade 1 or 2 in severity. Single oral doses of IDELA 150 mg were well tolerated in subjects with hepatic impairment and in healthy matched controls.

IDELA C_max was generally comparable in the subjects with moderate (CPT Class B) or severe (CPT Class C) hepatic impairment relative to healthy matched control subjects, while mean AUC was higher (58% to 60%). GS-563117 exposures were lower in subjects with moderate and severe hepatic impairment relative to matched healthy control subjects, likely due to lower formation in the setting of liver impairment. Overall, the observed changes in mean exposures of IDELA and GS-563117 are not considered to be clinically relevant. Exploratory analyses indicated no relevant relationships between the IDELA or GS-563117 plasma exposures and CPT score for subjects with moderate or severe hepatic impairment.

No clinically relevant changes in IDELA and GS-563117 exposures were observed in subjects with moderate or severe hepatic impairment versus matched healthy control subjects. Single oral doses of IDELA 150 mg were well tolerated.

Jin:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Hisoire:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.