Preclinical metabolism and pharmacokinetics of SB1317 (TG02), a potent CDK/JAK2/FLT3 inhibitor

• Published in: Drug metabolism letters Vol. 6; no. 1; p. 33
• Main Authors: Pasha, Mohammed Khalid, Jayaraman, Ramesh, Reddy, Venkatesh Pilla, Yeo, Pauline, Goh, Evelyn, Williams, Anthony, Goh, Kee Chuan, Kantharaj, Ethirajulu
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.03.2012
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological Availability; Caco-2 Cells; Cyclin-Dependent Kinases - antagonists & inhibitors; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - metabolism; Dogs; Female; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; Hepatocytes - enzymology; Hepatocytes - metabolism; Heterocyclic Compounds, 4 or More Rings - administration & dosage; Heterocyclic Compounds, 4 or More Rings - pharmacokinetics; Heterocyclic Compounds, 4 or More Rings - pharmacology; Humans; Inhibitory Concentration 50; Janus Kinase 2 - antagonists & inhibitors; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microsomes, Liver - metabolism; Rats; Rats, Wistar; Species Specificity; Tissue Distribution
• ISSN: 1874-0758

SB1317 (TG02) is a novel small molecule potent CDK/JAK2/FLT3 inhibitor. To evaluate full potential of this development candidate, we conducted drug metabolism and pharmacokinetic studies of this novel anti-cancer agent. SB1317 was soluble, highly permeable in Caco-2 cells, and showed > 99% binding to plasma from mice, dog and humans. It was metabolically stable in human and dog liver microsomes relative to mouse and rat. SB1317 was mainly metabolized by CYP3A4 and CY1A2 in vitro. SB1317 did not inhibit any of the major human CYPs in vitro except CYP2D6 (IC50=1 μM). SB1317 did not significantly induce CYP1A and CYP3A4 in human hepatocytes in vitro. The metabolic profiles in liver microsomes from preclinical species were qualitatively similar to humans. In pharmacokinetic studies SB1317 showed moderate to high systemic clearance (relative to liver blood flow), high volume of distribution ( > 0.6 L/kg), oral bioavailability of 24%, ∼ 4 and 37% in mice, rats and dogs, respectively; and extensive tissue distribution in mice. The favorable ADME of SB1317 supported its preclinical development as an oral drug candidate.