Pharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming growth factor beta receptor 1 inhibitor.

Autor: Parrish KE; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Swanson J; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Cheng L; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Luk E; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Stetsko P; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Smalley J; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Shu YZ; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Huang J; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Pabalan JG; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Sun Y; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Zvyaga T; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Cvijic ME; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Burke J; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Borzilleri R; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Murtaza A; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Augustine K; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA., Yang Z; Department of Metabolism and Pharmacokinetics, Bristol Myers Squibb, Research and Early Discovery, Princeton, New Jersey, USA.
Jazyk: angličtina
Zdroj: Biopharmaceutics & drug disposition [Biopharm Drug Dispos] 2021 Apr; Vol. 42 (4), pp. 137-149. Date of Electronic Publication: 2021 Jan 08.
DOI: 10.1002/bdd.2256
Abstrakt: Transforming growth factor beta (TGF-β) is a pleiotropic cytokine that has a wide array of biological effects. For decades, tumor biology implicated TGF-β as an attractive therapeutic target due to its immunosuppressive effects. Toward this end, multiple pharmaceutical companies developed a number of drug modalities that specifically target the TGF-β pathway. BMS-986260 is a small molecule, selective TGF-βR1 kinase inhibitor that was under preclinical development for oncology. In vivo studies across mouse, rat, dog, and monkey and cryopreserved hepatocytes predicted human pharmacokinetics (PK) and distribution of BMS-986260. Efficacy studies of BMS-986260 were undertaken in the MC38 murine colon cancer model, and target engagement, as measured by phosphorylation of SMAD2/3, was assessed in whole blood to predict the clinical efficacious dose. The human clearance is predicted to be low, 4.25 ml/min/kg. BMS-986260 provided a durable and robust antitumor response at 3.75 mg/kg daily and 1.88 mg/kg twice-daily dosing regimens. Phosphorylation of SMAD2/3 was 3.5-fold less potent in human monocytes than other preclinical species. Taken together, the projected clinical efficacious dose was 600 mg QD or 210 mg BID for 3 days followed by a 4-day drug holiday. Mechanism-based cardiovascular findings in the rat ultimately led to the termination of BMS-986260. This study describes the preclinical PK characterization and pharmacodynamics-based efficacious dose projection of a novel small molecule TGF-βR1 inhibitor.
(© 2020 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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