CNC1101 is a selective Poly ADP-Ribose Polymerase 1 (PARP1) inhibitor. In tumors with BRCA mutations, PARP1-selective inhibitors induce cell apoptosis through ‘synthetic lethality’.
In the previous study, we developed the LC-MS/MS bioanalytical method of CNC1101 and it met FDA guidelines. This method was successfully applied to pharmacokinetic studies. CNC1101 showed >98% plasma protein binding in rat, mouse, rabbit, dog, and human. It inhibited CYP450s 3A4. In addition, it was moderate to highly stable in mouse, dog, and human microsomes. CNC1101 was orally administered to rats and mice at doses of 3, 10, 30, and 100 mg/kg (mice only), it exhibited linear pharmacokinetics in both species. The bioavailability was 61.3-83.3% in rats and 26.2-37.3% in mice, respectively. Upon oral administration of CNC1101 to rats at 3 mg/kg, high exposure was observed in the adrenal glands and liver, with K_p values greater than 1 in major organs, except the eyes and brain. The K_p values of plasma to brain were 0.887 and 0.196 in rats and mice, respectively, but the free fractions of plasma and brain homogenates showed similar values, indicating interspecies differences in brain distribution.
In conclusion, a pharmacokinetic study was successfully conducted to develop a PARP1-selective oral anticancer drug, and these results will be valuable for achieving clinical approval of CNC1101.