Abstract 2730: Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling

Abstract Conventional chemotherapy with maximum tolerated dose (MTD) has shown confident anti-cancer effect and when combined with targeted therapy, immunotherapy. Yet, understanding about how the MTD regimen is optimized has lacked due to its high tumor burdens. In this study, the oral doxorubicin (DOX) formulation was shown to improve oral bioavailability by 12.1% and sustain the metronomic concentration through the flexible protocol. Since the optimizing dose and schedules of DOX in metronomic chemotherapy (MCT) is essential to maximize efficacy and minimize toxicity, which is determined by the exposure of drugs based on pharmacokinetic-pharmacodynamic (PK/PD) correlation, we developed an integrated systemic mathematical model that can evaluate the anti-tumor effect and the toxicity of oral DOX formulation simultaneously. Oral physiologically-based pharmacokinetic (PBPK) models were established with dose dependency, and creatine kinase-MB (CK-MB) and tumor growth profiles were assessed as markers for toxicodynamic (TD) and PD models, respectively. Each model was validated and then integrated into the PK-TD/PD model and the effects of various oral metronomic regimens were predicted. In conclusion, the finalized oral metronomic dosing regimen (10 mg/kg, QD) showed 83.3% tumor growth inhibition without cardiotoxicity. In this study, we defined the MCT regimen using a mathematical model and suggested a dose selection method for developing oral drugs from injections, to efficiently utilize the preclinical results and apply to clinical practice. Citation Format: Seho Kweon, Yoo-Seong Jeong, Yoon Gun Ko, Seung Woo Chung, Ha Kyeong Lee, Suk-Jae Chung, Youngro Byun, Sang Yoon Kim. Metronomic dose-finding approach of oral chemotherapy by experimentally-driven integrated mathematical modeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2730.