Pharmacokinetics, Metabolism and Excretion Of Idelalisib

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. Following oral administration of IDELA in dogs, ∼88% of the administered dose was recovered in the feces, predominantly as GS-563117 (33%), an oxidative metabolite of IDELA. The objective of the present study was to determine the mass balance/recovery, metabolite profile, and pharmacokinetics of IDELA and its metabolite in humans following administration of a single, oral dose of radiolabeled IDELA.

Healthy male subjects (N = 8) were administered a single dose of IDELA (150 mg) containing 100 µCi of [¹⁴C]IDELA. Blood, urine, and feces samples were collected up to a maximum of 21 days or until the following criteria were met: ≥ 90% of administered dose recovered in feces and urine, <1% of dose was present in consecutive sampling intervals, and plasma radioactivity in consecutive samples were ≤ 2-fold background or urine/feces sampling was discontinued. Concentrations of IDELA and GS-563117 were measured using LC/MS/MS and total radioactivity assessed by LSC. Metabolite profiling was performed in urine, feces, and plasma samples at selected timepoints. Safety assessments were performed throughout the study.

All 8 subjects completed in the study. Two drug-related, mild (Grade 1) adverse events were observed in one subject (lower abdominal pain and flatulence). All laboratory abnormalities were mild in severity and one subject experienced grade 2 decreased neutrophil counts. The mean (SD) recovery of [¹⁴C]-radioactivity was 92% (1.7%), with 78% (3.9%) in feces and 14% (2.9%) in urine. GS-563117 was the predominant species in feces (44% of total quantified radioactivity) and urine (49% of total quantified radioactivity). Peak plasma radioactivity was observed at ∼ 2 hours post-dose. Over the 24-hour period following IDELA administration, the circulating radioactivity consisted entirely of IDELA (38%) and its metabolite, GS-563117 (62%), formed via aldehyde oxidase. The whole blood-to-plasma concentration ratio of [¹⁴C]-radioactivity was ∼0.5, indicating that IDELA and its metabolite are predominantly distributed to plasma, relative to the cellular components of the blood. Low levels of other metabolites, including hydroxylation and glucuronidation products, were observed in urine and feces.

IDELA was eliminated primarily in the feces and oxidation to GS563117 was the major metabolic pathway. IDELA and GS563117 were the only circulating species observed in plasma, and GS563117 was the main species observed in feces and urine.

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