Preclinical assessment of the PI3Kα selective inhibitor inavolisib and prediction of its pharmacokinetics and efficacious dose in human.

Autor:	Salphati L; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Pang J; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Plise EG; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Cheong J; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Braun MG; Chemistry, Genentech, Inc., South San Francisco, CA, USA., Friedman LS; Cancer Signaling, Genentech, Inc., South San Francisco, CA, USA., Hong Thibodeau R; Translational Oncology, Genentech, Inc., South San Francisco, CA, USA., Jaochico A; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Johnson R; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Liu N; Departments of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Nannini M; Translational Oncology, Genentech, Inc., South San Francisco, CA, USA., Sampath D; Translational Oncology, Genentech, Inc., South San Francisco, CA, USA., Song K; Cancer Signaling, Genentech, Inc., South San Francisco, CA, USA., Hannan EJ; Chemistry, Genentech, Inc., South San Francisco, CA, USA., Staben ST; Chemistry, Genentech, Inc., South San Francisco, CA, USA.
Jazyk:	angličtina
Zdroj:	Xenobiotica; the fate of foreign compounds in biological systems [Xenobiotica] 2024 Dec 04, pp. 1-13. Date of Electronic Publication: 2024 Dec 04.
DOI:	10.1080/00498254.2024.2415103
Abstrakt:	1. Small molecule inhibitors of the PI3K pathway have been extensively investigated as potential anticancer agents. Among the effectors in this pathway, PI3Kα is the kinase most frequently associated with the development of tumours, through mutations and amplifications of the PIK3CA gene encoding the p110α catalytic subunit.2. Inavolisib (GDC-0077) is a potent and PI3Kα-selective inhibitor that also specifically triggers the degradation of the mutant p110α protein.3. We characterised inavolisib ADME properties in preclinical in vitro and in vivo studies, assessed its efficacy in the PIK3CA mutant KPL-4 breast cancer xenograft model, and predicted its pharmacokinetics and efficacious dose in humans.4. Inavolisib had a moderate permeability (1.9•10 -6  cm/s) in MDCK cells and was a P-gp and Bcrp1 substrate. It appeared metabolically stable in hepatocytes incubations from human and preclinical species. The systemic clearance was low in mouse, monkey and dog and high in rat. Oral bioavailability ranged from 57.5% to 100%. Inavolisib was efficacious in the KPL-4 sub-cutaneous xenograft model.5. The PK/PD model parameters estimated from the efficacy study, combined with PBPK model-predicted human PK profiles, projected that a dose of 3 mg could lead to clinical response. Inavolisib is currently being tested in phase 3 trials.
Databáze:	MEDLINE
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