S. Sahasranaman, R. A. Graham, L. Salphati, J. Hsu, X. Lu, M. Gates, D. Amin, 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. In vitro studies indicate that taselisib is primarily metabolized by CYP3A4. A DDI study was conducted to evaluate this risk by comparing the PK of taselisib when given alone and when co-administered with a strong CYP3A4 inducer (rifampin) or inhibitor (itraconazole).
METHODS: A Phase I, open-label, 2-period, fixed sequence, 2-arm drug interaction study was conducted in healthy subjects. In Arm A (N=16), 3 mg taselisib was dosed alone on Day 1 followed by rifampin (600 mg qd) dosing on Days 10 through 22. On Day 15, 3 mg taselisib was co-administered with rifampin. In Arm B (N=16), 3 mg taselisib was dosed alone on Day 1 followed by itraconazole (200 mg qd) dosing on Days 12 through 22. On Day 15, 3-mg taselisib was co-administered with itraconazole.
RESULTS: After administration of rifampin, the Cmax and AUC0-inf for taselisib were decreased by 16% (geometric mean ratio [GMR]: 0.84; 90% confidence interval [CI]: 0.74 to 0.97) and 24% (GMR: 0.76; 90% CI: 0.70 to 0.82), respectively. After administration of itraconazole, the Cmax and AUC0-inf for taselisib were increased by 9% (GMR: 1.09; 90% CI: 0.90 to 1.31) and 49% (GMR: 1.49; 90% CI: 1.28 to 1.73), respectively.
CONCLUSION: The results indicate taselisib PK is impacted by induction and inhibition of CYP3A4; however, the effect was only modest. Taselisib is not a sensitive CYP3A4 substrate and the magnitude of change in taselisib Cmax and AUC0-inf was lower than 2-fold when administered with rifampin or itraconazole.