The Pharmacokinetics and Safety Of Idelalisib In Subjects With Severe Renal Impairment

Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. Pharmacokinetics of IDELA and its major metabolite GS-563117 have been assessed in a number of clinical studies in healthy subjects and patients with hematologic malignancies. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on a human mass balance study, renal elimination plays a minor role on elimination of IDELA (∼ 15% of dose excreted in urine). The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with severe renal impairment following administration of a single oral dose of IDELA.

Subjects with severe renal impairment (RI) (eGFR 15 – 29 ml/min) and healthy controls (eGFR ≥ 80 ml/min) matched for age, gender, and body mass index received IDELA 150 mg single dose. Blood and urine 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 renal impairment group 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 12 subjects were enrolled in the study. The majority of subjects were female, white, and of nonHispanic/Latino ethnicity, and the median age was similar between the 2 groups (65 years of age for the severe group and 63 years for the healthy control group). Study treatments were generally well tolerated. Overall, 6 of 12 subjects (50.0%; 1 subject with severe renal impairment and 5 healthy matched control subjects) reported a total of 10 AEs; all were Grade 1 (mild) in severity. The most frequently reported AE was headache followed by nausea. No clinically significant abnormal changes were observed in vital signs (temperature, pulse, blood pressure, respiratory rate) and ECG results from baseline. Single oral doses of IDELA 150 mg were well tolerated.

Following single oral administration of IDELA 150 mg, IDELA AUC_last, AUC_inf, and C_max geometric least-squares mean ratio were 127%, 127%, and 105%, respectively, between subjects with severe renal impairment relative to matched control subjects (Table 1). Consistently, GS-563117 AUC_last, AUC_inf, and C_max geometric least-squares mean ratio were 124%, 124%, and 96%, respectively, between subjects with severe renal impairment relative to matched control subjects. These minimal changes observed in IDELA and GS-563117 exposure in severe renal impairment vs matched control subjects are not considered to be clinically meaningful. There were no relevant relationships between IDELA or GS-563117 exposures and baseline estimated creatinine clearance.

There were no clinically relevant differences in the pharmacokinetics of IDELA or its primary metabolite GS563117 between subjects with severe renal impairment and matched healthy control subjects following a single oral dose of IDELA 150 mg. Dose adjustments for IDELA are not considered necessary in subjects with mild, moderate, or severe renal impairment following oral administration. 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.