Pharmacokinetics and Safety Of Idelalisib, a Novel PI3Kδ Inhibitor, In Japanese and Caucasian Subjects

PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-cell malignancies. Idelalisib (IDELA), currently in Phase 3 clinical development, is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. 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. The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in healthy Japanese and Caucasian subjects following administration of IDELA in support of clinical development in cancer patients in Japan.

Healthy Caucasian and first-generation descent Japanese subjects (N = 10/group) were enrolled at a single center in the US and administered a single dose of IDELA (150 mg) under fed condition. Blood samples were collected and levels of IDELA and GS-563117 were measured using a validated LC/MS/MS method. Safety assessments were performed throughout the study.

All 20 subjects completed the study and 5 of 10 Japanese subjects (50.0%) and 3 of 10 Caucasian subjects (30.0%) were female. Study treatments were generally well tolerated. Two Japanese subjects and 2 Caucasian subjects reported at least 1 treatment-emergent AE. All treatment-emergent AE were mild in severity (all grade 1 except one grade 2 diarrhea in a Japanese subject which occurred on day 2 and resolved on day 6 post dose without treatment). All individual treatment-emergent laboratory abnormalities were Grade 1 or 2 in severity. Following a single oral administration of IDELA 150 mg, the exposures (AUC_inf, AUC_last, and C_max) of IDELA and GS-563117 were slightly higher in Japanese subjects compared with Caucasian subjects (Table 1). The median t_1/2 values for IDELA and GS-563117 were comparable. Overall, the observed exposures were in the range of those observed in other IDELA Phase 1 studies with non-Japanese subjects, and the differences between Japanese and Caucasian subjects are not considered clinically relevant.

There were no clinically relevant differences in the pharmacokinetics of IDELA and GS563117 between Japanese and Caucasian subjects following a single oral dose of IDELA 150 mg. No dose adjustment is needed for IDELA 150 mg treatment in Japanese subjects following oral administration. Single oral doses of IDELA 150 mg were well tolerated in Japanese and Caucasian subjects.

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