Abstract PO-115: Co-modeling of calcipotriol and paclitaxel in blood and tumor of KrasG12D mouse model of pancreatic cancer after i.v bolus dose of a micellar co-formulation

Abstract

Abstract Stroma-modulating agents in combination with chemotherapy have emerged as a potential treatment for pancreatic cancer, and we are developing a combination therapy of Calcipotriol (Cal) and paclitaxel (PTX). Cal, a stroma-modulating agent de- activates the cancer associated fibroblasts, shifting the tumor microenvironment into a dynamic milieu that aids PTX delivery. However, Cal causes hypercalcemia. To mitigate toxicity and further improve tumor accumulation, we developed a micellar co-formulation (M-Cal/PTX). A biodistribution study in tumor, liver and spleen of an orthotopic Kras mouse model showed that 24 h after a single IV bolus dose (0.5 mg/kg Cal, 5 mg/kg PTX), Cal from M-Cal/PTX (M-Cal) was measurable in the tumors and livers but not blood. In contrast, Cal was not measurable in these tissues 24 h after IV dose of non-formulated free Cal. Even though PTX could be measured in blood 24 h after a single dose in both formulated and non-formulated groups, it was only measurable in the tumors of mice administered M-Cal/PTX. To better understand the distribution kinetics of M-Cal/PTX, we co-modeled blood and tumor concentrations using Phoenix NLME. Our analysis showed PK differences of M-Cal in healthy versus tumor-bearing mice. The elimination half-life (t1/2) of M-Cal in diseased mice was >4X shorter than that in healthy ones (0.089 h vs 0.38 h), which corresponded with increased uptake into the peripheral tissues. The uptake rate into the spleen was the highest; however, M-Cal persisted in tumor and liver because of the slow eliminations from these tissues. Unsurprisingly, our model estimated that the blood AUC0-inf in diseased mice was 5X less than that in the healthy counterparts, resulting from the significantly shorter t1/2. A similar analysis of PTX from M-Cal/PTX showed that the elimination half-life was about 2X shorter in diseased mice when compared to their healthy counterparts (0.58 h vs 1.2 h). This corresponded with a modest blood AUC0-inf decrease in tumor-bearing mice. Of the tumor and two organs evaluated, our model estimated PTX liver uptake to be the highest, followed by the spleen and then tumor. Nonetheless, PTX could still be measured in all three sites 24 h after M-Cal/PTX injection. We conclude that 1) PK of Cal and PTX from M-Cal/PTX differ between diseased and healthy mice, with a faster elimination in the tumor-bearing mice. 2) Reduced Cal AUC0-inf in blood and its presence in tumors are expected to offer the potential merits of a reduced systemic toxicity and increased efficacy respectively, because Cal toxicity is directly related with the elevated systemic exposure that exacerbates off-target vitamin D receptor activation. Future studies will focus on proof-of-concept efficacy and toxicity studies to demonstrate the potential therapeutic merits of our combination formulation regimen in the orthotopic Kras mouse model of pancreatic cancer. Citation Format: Victor Lincha, Jun Zhao, Xiaoxia Wen, Lillian Duong, Chun Li, Diana Chow. Co-modeling of calcipotriol and paclitaxel in blood and tumor of KrasG12D mouse model of pancreatic cancer after i.v bolus dose of a micellar co-formulation [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-115.