Abstract 4906: Effect of gender on the rodent pharmacokinetics of ON 123300, a dual inhibitor of ARK5 and CDK4/6, for the treatment of cancer

Purpose: To evaluate gender differences in the metabolism of ON 123300 in rats in vitro and in vivo. ON 123300, a novel small molecule dual inhibitor of the c-MYC activated kinases ARK5 and CDK4/6, is being developed by Onconova Therapeutics, Inc. as a novel anti-cancer drug candidate. Methods: In vitro metabolism experiments were performed in rat liver microsomes from male and female donors. ON 123300 was incubated with microsomes, and samples were withdrawn at specified times over 60 minutes and, immediately quenched and centrifuged. The supernatant was analyzed for ON 123300 and its metabolites by HPLC. An in vivo pharmacokinetic study was performed in male and female SD rats. ON 123300 was administered as a single oral dose (100 mg/kg), and blood samples were collected over 24 hours. ON 123300 concentrations were measured by LC-MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis. Results: The results are provided in Table 1. ON 123300 displayed more rapid microsomal degradation in vitro (increase of Clint) in males compared to females. This translated into a significantly higher exposure of ON 123300 (3 fold increase of AUC) following oral administration to female rats. Based on these results, the higher plasma concentrations observed in females can be primarily attributed to reduced hepatic clearance compared to males. Conclusions: Gender differences in pharmacokinetics and pharmacodynamics can potentially impact the design of safe and effective dosing regimens for treatments. This investigation demonstrated a significantly lower metabolism of ON 123300 in female rats, which resulted in dramatically high systemic exposure. Additional testing is warranted to assess the potential clinical implications of these findings. Table 1. ON 123300 In Vitro and In Vivo Pharmacokinetic Parameters apredicted from venous equilibration model assuming rat blood flow = 13.8 ml/min, 99% protein binding and blood:plasma ratio = 1 Citation Format: Chen Ren, Jennypher Mudunuru, David Taft, Manoj Maniar. Effect of gender on the rodent pharmacokinetics of ON 123300, a dual inhibitor of ARK5 and CDK4/6, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4906.