Pharmacodynamics-based approach for efficacious human dose projection of BMS-986260, a small molecule transforming growth factor beta receptor 1 inhibitor.
Adenocarcinoma
/ drug therapy
Animals
Cell Line, Tumor
Colonic Neoplasms
/ drug therapy
Dogs
Dose-Response Relationship, Drug
Female
Hepatocytes
/ metabolism
Humans
Macaca fascicularis
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neoplasms, Experimental
/ drug therapy
Protein Kinase Inhibitors
/ administration & dosage
Rats
Rats, Sprague-Dawley
Receptor, Transforming Growth Factor-beta Type I
/ antagonists & inhibitors
Species Specificity
Tissue Distribution
PK/PD
TGF-β
TGF-β receptor inhibition
human efficacious dose projection
preclinical PK
Journal
Biopharmaceutics & drug disposition
ISSN: 1099-081X
Titre abrégé: Biopharm Drug Dispos
Pays: England
ID NLM: 7911226
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
revised:
04
11
2020
received:
07
08
2020
accepted:
01
12
2020
pubmed:
24
12
2020
medline:
15
12
2021
entrez:
23
12
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Protein Kinase Inhibitors
0
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
137-149Subventions
Organisme : Bristol Myers Squibb
Informations de copyright
© 2020 John Wiley & Sons Ltd.
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