Abstract 3786: Physiologically based pharmacokinetic model of CFAK-C4 disposition in mice for understanding its anti-tumor efficacy

Abstract

Abstract Objective: Preclinical studies have demonstrated that CFAK-C4 has anti-tumor efficacy in a variety of malignancies. To maximize its efficacy, it is necessary to understand the pharmacokinetic (PK) properties of CFAK-C4 in the body. A PK study was conducted to characterize CFAK-C4 disposition in plasma and various tissues, including brain, heart, liver, lung, muscle, spleen, and sternum. Subsequently, a physiologically-based pharmacokinetic (PBPK) model was developed to simultaneously characterize and predict plasma and tissue CFAK-C4 concentrations and thus help guide future dosing strategies alone and in combination. Methods: Female CD-1 mice received a single IP injection of CFAK-C4 with a dose of 50mg/kg, and then plasma and tissue samples were collected at serial time points after injection. Three mice were sacrificed at each time point. CFAK-C4 concentrations were determined by a validated LC-MS/MS method. Noncompartmental PK analysis was performed using WinNonlin (Pharsight, Version 5.3) for PK parameters. CFAK-C4 concentration-time profiles were fitted with a PBPK model composed of compartments for plasma, all the measured tissues, peritoneum, and a remainder compartment which represented all other tissues where CFAK-C4 was not measured, using ADAPT5 (BMSR, USC). The PBPK model was assessed by goodness-of-fit plots together with agreement of estimated parameters with noncompartmental analysis. Results: CFAK-C4 concentrations followed a monoexponential decay in plasma, while there was a longer elimination phase observed in tissues. As a result, CFAK-C4 concentration-time profiles in plasma and tissues were simultaneously fitted into a plasma-flow-rate-limited PBPK model successfully. Partition coefficients (Kp), as a measure of the extent of tissue distribution, and plasma clearance (Cl) were estimated by the PBPK model, while the volumes of distribution and plasma flow rates of tissues were fixed to physiological values. The model predicts that CFAK-C4 can be well distributed to various tissues quickly, and Cmax is achieved within half an hour after IP injection. The estimated Cl, 0.111 (±7.4%) l/h, was similar to the value from non-compartmental analysis (NCA) (0.0925 L/h). The model also predicts CFAK-C4 has the highest penetration to lung, with a Kp of 28.1 (±15.2%), followed by brain, with a Kp of 16.6 (±11.6%), and it has the lowest penetration to muscle, with a Kp of 3.6 (±8.3%). Conclusions: The wide tissue distribution of CFAK-C4 provides a great advantage for maximizing its anti-tumor efficacy. The PBPK model predicts CFAK-C4 plasma and tissue concentrations reasonably well. This PBPK model will be used as a tool to build PK/PD models to characterize the temporal relationship between CFAK-C4 pharmacokinetics and its antitumor efficacy and thus help decide future dosing strategies for the treatment of various malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3786. doi:1538-7445.AM2012-3786