Effect of Gender on the Pharmacokinetics of ON 123300, A Dual Inhibitor of ARK5 and CDK4/6 for the Treatment of Cancer, in Rats
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Background and Objectives
ON 123300, a small molecule dual inhibitor of the c-MYC activated kinases ARK5 and CDK4/6, is being developed as a novel drug candidate for the treatment of cancer. The objective of this research was to evaluate gender differences in the in vitro metabolism and in vivo systemic exposure of ON 123300 in rats.
In vitro metabolism experiments (n = 2/group) were performed in rat liver microsomes from male and female donors. ON 123300 bislactate (final concentration 10 µM) was incubated with 0.5 mg/mL microsomes, and samples (100 µL) were withdrawn at specified incubation times over a period of 60 min, and immediately quenched and centrifuged. The supernatant was analyzed for ON 123300 and its metabolites by HPLC. ON 123300 (bislactate salt) pharmacokinetics were evaluated following intravenous (i.v.) (30 s infusion, 5 and 10 mg/kg) or oral administration (25 and 100 mg/kg) to male and female Sprague–Dawley rats (250–300 g). Following dosing, blood samples were collected over a time period up to 24 h. ON 123300 plasma concentrations were measured by LC–MS/MS. Pharmacokinetic parameters were estimated by non-compartmental analysis. Plasma and microsomal binding of ON 123300 and blood:plasma ratio were also determined.
ON 123300 displayed more rapid microsomal degradation in vitro in males compared to females, as reflected in intrinsic clearance (181 vs 53.1 µL/min/mg). This translated into a significantly higher exposure of ON 123300 following oral administration to female rats, with the area under the curve (AUC) increasing nearly 3-fold (5617 ± 1914 ng·h/mL) compared to males (AUC = 1965 ± 749 ng·h/mL). This gender effect was less pronounced following i.v. dosing, where the AUC was ~ 2-fold higher in females. Based on these results, the higher plasma exposure observed in females can be primarily attributed to reductions in both hepatic clearance and presystemic metabolism compared to males.
This investigation demonstrated a significantly lower metabolism of ON 123300 in female rats, which resulted in high systemic exposure. Additional testing is warranted to assess the potential clinical implications of these findings.
Compliance and Ethical Standards
This research was funded by Onconova Therapeutics, Inc.
Conflict of interest
J. Mudunuru, no conflicts; C. Ren, employed by Onconova Therapeutics, Inc.; D. Taft, received grant support from Onconova Therapeutics, Inc.; M. Maniar, employed by Onconova Therapeutics, Inc.
The Institutional Animal Care and Usage Committee (IACUC) of Long Island University (Brooklyn Campus) approved the experimental protocol for the animal experiments. All animal procedures were conducted in accordance with the United States National Research Council “Guide for the Care and Use of Laboratory Animals”.
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