Abstract 4923: Pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice

Abstract

Abstract Metastasis is the principal cause of death for most cancer patients; however, effective treatment options are limited. The Rho GTPases Rac and Cdc42 are critical regulators of cancer cell migration and invasion; processes required for metastatic progression. Hence, targeting of these pivotal regulators is a rational approach for novel metastasis focused therapy design. We previously characterized the small molecule MBQ-167 as a novel Rac/Cdc42 inhibitor that inhibits mammary tumor growth and metastasis in immunocompromised mice by ~90%, which is ten times more potent than other currently available Rac inhibitors (Humphries-Bickley, et al., 2017). However, further studies are needed to determine the pharmacokinetic (PK) parameters of MBQ-167 in rodents to understand the mechanisms of drug distribution and elimination of this compound. The purpose of this study was to determine the pharmacokinetics and bioavailability of MBQ-167 in a single dose input scheme (10 mg/kg BW) following intraperitoneal (IP) and oral gavage (PO) administration. The drug was administered to BALB/c mice (4 mice/group) and plasma was collected at 0.5, 1, 3, 6, 9, and 12 hours after IP or PO administration. We developed and validated a bioanalytical method using supercritical fluid chromatography (SFC) coupled with electrospray ionization tandem mass spectrometry (MS/MS) for the detection of MBQ-167 in plasma. SFC-MS/MS was selected because it uses supercritical carbon dioxide (SCO2) as the mobile phase and offers advantages such as high sensitivity, increased resolution, and rapid analysis times. Pharmacokinetic parameters were obtained by mono-compartmental and bi-compartmental analysis for IP and PO dosing respectively using WinNolin® software, Version 7.0. Preliminary pharmacokinetic analysis revealed that the area under the curve (AUC0-∞) was 749 ng·hr/mL and 255 ng·hr/mL for IP and PO dosing respectively. The elimination half-life (t1/2) was 2.4 hours for IP dosing and the mean residence time (MRT) was 3.4 hours and 2.3 hours for the IP and PO dosing respectively. The maximum plasma drug concentration (Cmax) was 220 ng/mL after IP administration, compared to 127 ng/mL following PO administration. Furthermore, the time-to-peak for both administration routes was 30 minutes. The relative bioavailability of MBQ-167 after oral gavage administration was 34%. This study presents the first analysis of the pharmacokinetics of the Rac/Cdc42 inhibitor MBQ-167 in mice and it supports the continued development of this drug as a potential anti-cancer therapeutic. Citation Format: Maria del Mar Maldonado, Linette Castillo-Pichardo, Joseph Bloom, Jorge Duconge, Jose F. Rodriguez-Orengo, Eliud Hernandez-O'Farrill, Cornelis Vlaar, Suranganie Dharmawardhane. Pharmacokinetics of the metastatic cancer inhibitor MBQ-167 in mice [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 4923.