Introduction: The 5-year survival rate for Pancreatic Ductal Adenocarcinoma (PDAC) remains 7%. An emerging treatment strategy involves the combination of vitamin D receptor (VDR) ligands with chemotherapeutic agents to re-program the activated cancer-associated fibroblast (CAFs). Calcipotriol (CAP), a synthetic analogue of vitamin D can reprogram CAFs, but is toxic with side effects including cachexia and edema. Due to the abundance of the VDR in the body, diminished plasma exposure and elimination of calcipotriol together with enhanced accumulation in the tumor are desirable to reduce toxicity and increase efficacy. We propose to achieve this with a slow-releasing micellar nanoformulation with a well-controlled size to take advantage of the leaky tumor fenestrations and enhance delivery. Method: 8-week old male C57BL/6 mice were administered with either formulated or non-formulated single IV bolus dose of CAP and paclitaxel (PTX). Drugs from blood samples were extracted, and simultaneously quantified using validated LC-MS/MS assay. Pharmacokinetic modeling was performed with Phoenix® WinNonlin (8.0) using 2-compartment model. Results: Our co-formulation of CAP and PTX resulted in >2-fold decrease in plasma exposure (AUC) and 5-fold reduction of peak concentration (Cmax) of CAP. Similarly, PTX AUC and Cmax were halved in mice administered with the formulated drugs. The PTX total clearance (CL) was similar between both groups, but CAP CL was 5-fold lower in formulation-administered mice. Further, CAP elimination (k10) from central compartment and from central to peripheral compartments (k12) were 2 and >3-fold slower, respectively, in the formulation group. The reverse elimination (k21) are similar. Similarly, the k10 of PTX was almost halved, while the k12 was 44-fold slower in mice receiving formulated drugs. The reverse elimination from the peripheral to the central compartment (k21) for formulated PTX is almost 10 times slower than in the mice receiving non-formulated PTX. Conclusion: Our micellar co-formulation of CAP and PTX is able to reduce total clearance of these agents from the systemic circulation. Further, rate constants derived show that PTX elimination from the systemic circulation to tissues is very slow and we expect this to correlate with an extended duration of action of this drug. Finally, our formulation halved the systemic exposure and peak concentrations of CAP that should lead to a more favorable safety profile of this agent. Ongoing work will focus on studying the pharmacokinetics of co-formulated CAP and PTX in a larger cohort of animals and we eventually hope to demonstrate the therapeutic merits of our nanoformulation strategy in pancreatic tumor-bearing mice.
Citation Format: Victor R Lincha, Jun Zhao, Chun Li, Diana S-L Chow. Pharmacokinetic analysis of co-formulation of calcipotriol and paclitaxel for pancreatic ductal adenocarcinoma shows reduced systemic exposures and eliminations: Implications for safety and efficacy [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D052.