S. Sahasranaman, S. Ma, J. Hsu, M. Gates, Y. Ran, K. Zhang, P. Yehl, L. Salphati, X. Ding, D. Bradford, M. Dresser, J. Ware; Genentech, Inc, South San Francisco, CA

BACKGROUND: Taselisib is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. A study to assess the absolute bioavailability (aBA) of taselisib and the absorption, metabolism, and excretion of [14C]-taselisib was conducted.
METHODS: A Phase I, open-label, 2-arm study was conducted in healthy male subjects. In Arm A (aBA), subjects (N=8) received a single 3 mg oral capsule dose of taselisib followed 4 hours later by a single 3 μg IV dose (3 minute manual IV push) of [14C]-taselisib (200 nCi). PK samples were collected up to 240 h post dose. In Arm B (ADME), subjects (N=6) received a single 3 mg oral capsule dose of [14C]-taselisib (200 μCi). Blood, urine and feces samples were collected up to 336 h post dose.
RESULTS: In Arm A, aBA was estimated to be 62.2% (CV: 23%) for the 3 mg taselisib capsule. Mean T1/2 were comparable in subjects after IV (37 h) and oral (40 h) dosing. In Arm B, mean recovery of radioactivity in feces and urine was 88.6% (range 80.7% to 105%) and 15% (10.6% to 19.9%), respectively. Unchanged taselisib was the only detectable radioactive peak in pooled 0-96 hour human plasma from all subjects. No [14C]-taselisib related metabolites were present in systemic circulation. Taselisib was mainly cleared as unchanged drug in feces and in urine.
CONCLUSION: Taselisib undergoes minimal metabolism and was the only species detected in plasma after oral administration. Following oral administration, taselisib appears to undergo significant biliary excretion based on the aBA estimate of 63.8% and 88.6% recovery of radioactivity in the feces.