(W1130-10-67) Effects of Abcb1 and Abcg2 on the Brain Penetration, Biliary Disposition, and Intestinal Secretion of the PI3K Inhibitor Taselisib

Purpose: Taselisib (GDC-0032) is a potent and selective inhibitor of the PI3K α and δ isoforms that shows greater potency against the mutated PI3Kα than the wild-type kinase. It is active in vitro in tumor cells bearing mutated p110α and efficacious in vivo in xenograft models of PIK3CA-mutated breast cancel models. The purpose of our studies was to assess the impact of efflux transporters on the absorption and disposition of taselisib. Studies were conducted in vitro in MDCK cells and in vivo in wild type (WT) and in P-glycoprotein (Pgp) and/or Bcrp knockout (KO) mice and rats.

Methods: Studies were conducted in vitro in MDCK cells and in vivo in wild type (WT) and in P-glycoprotein (Pgp) and/or Bcrp knockout (KO) mice and rats.

Results: In vitro, taselisib was identified as a substrate of Pgp and Bcrp in MDCK cells over expressing these efflux transporters, with efflux ratios of 65 and 37, respectively. The inhibitors elacridar, for Pgp, and Ko143, for Bcrp, reduced the efflux ratios to approximately 1. In mice, following intravenous (IV) administration (1 mg/kg), AUC increased 1.8-, 3.7- and 7-fold in Pgp KO, Bcrp KO and Pgp/Bcrp KO (TKO) animals, respectively, compared to the WT. Following oral administration (1 mg/kg) of taselisib, AUC and C_max increased 12- and 6-fold, respectively, in TKO vs WT mice. Brain penetration was not impacted in single KO mice, with similar brain-to-plasma ratio (Kp) of 0.012 to 0.014 in WT, Pgp and Bcrp KO. In contrast, Kp increased by 8-fold, to 0.091, in TKO mice and brain concentration 1 hour post-dose increased from 0.02 µM in WT to 0.37 µM in TKO. Biliary elimination, measured in gall bladder cannulated (GBC) mice, decreased by 16% in Pgp KO and by more than 90% in Bcrp KO mice compared to WT following IV administration. Interestingly, taselisib was still recovered in feces of GBC WT animals, suggesting direct intestinal secretion. In rats, comparable results were obtained, with a 2.7-fold increase in AUC in Mdr1a-Bcrp KO animals vs. WT following IV administration (1 mg/kg). Biliary elimination (13% of dose) was unchanged in Pgp KO rats vs. WT, while it decreased by 60% (to 5% of dose) in Bcrp KO animals. The fraction of taselisib recovered in feces of BDC WT rats suggested that direct intestinal secretion accounted for more than 50% of fecal elimination.

Conclusion: The absorption and disposition of taselisib, a Pgp and Bcrp substrate, were markedly impacted by these efflux transporters in mice and rats. As could be expected, brain penetration was also impaired. However, despite a 10-fold increase in brain concentration in TKO mice, Kp remained low (~0.1). Biliary elimination appeared mainly dependent on Bcrp in both species. These studies also revealed the importance of direct intestinal secretion of taselisb by Pgp and Bcrp, particularly in rats.