Abstract 4519: Development of a whole body physiologically-based pharmacokinetic (PBPK) model with individualized tumor compartment for topotecan (TPT) in mice bearing neuroblastoma (NB)

Abstract

Abstract Intratumoral pharmacokinetic (PK) and pharmacodynamic (PD) heterogeneity contribute to variability in NB tumor response to chemotherapy and can be responsible for tumor relapse. Herein we propose to develop a whole body PBPK model with an individualized tumor compartment to derive individual tumor specific concentration-time profiles for the NB standard of care drug TPT. This model can then relate intratumoral heterogeneity in tumor blood flow to PD response and antitumor effects. PK studies of TPT (0.6, 1.25, 5, and 20 mg/kg, IV bolus) will be performed in CD1 nude mice (n = 3 mice/time point) bearing orthotopic NB (NB5) xenograft. Blood samples will be collected at predetermined time points using cardiac puncture, and plasma separated and stored until analysis. Animals will be perfused using saline solution to remove residual blood, and tissue samples including tumor, muscle, adipose, bone, liver, gallbladder, kidney, spleen, lungs, brain, heart, duodenum, and large intestine collected. TPT concentrations in plasma and tissue homogenate samples will be quantified using a validated HPLC fluorescence spectrophotometry method. Tumor samples will be divided into two sections each, one for TPT quantification and one for immunohistochemistry of PD markers for DNA damage (γ-H2AX) and apoptosis (CASP3). A cohort of mice will be used to quantify tumor blood flow using contrast-enhanced ultrasound (CEUS) using MicroMarker® microbubbles prior to dosing the mice for the PK study. TPT plasma and tissue concentration-time data will be used to develop the whole-body PBPK model with an individualized tumor compartment using NONMEM. Individual tumor perfusion data obtained using CEUS will be combined with the PBPK model to derive tumor specific concentration-time profiles. A preliminary study conducted in non-tumor bearing mice receiving TPT 5 mg/kg showed that TPT plasma and tissue concentration-time data were reasonably described by our PBPK model. As expected from our previous studies, the brain tissue was found to have the lowest exposure to TPT with a brain to plasma partition coefficient (Kp,brain ∼ 8%). We also observed high permeability of TPT (Kp > 1) into the gallbladder, duodenum, large intestine, spleen, liver and kidney. In future we will study the correlations between individual tumor concentrations based on our comprehensive PBPK model and γ-H2AX and CASP3 activity. Citation Format: Yogesh T. Patel, Megan O. Jacus, Abbas Shirinifard, Abigail D. Davis, Suresh Thiagarajan, Stacy L. Throm, Vinay M. Daryani, Andras Sablauer, Clinton F. Stewart. Development of a whole body physiologically-based pharmacokinetic (PBPK) model with individualized tumor compartment for topotecan (TPT) in mice bearing neuroblastoma (NB). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4519. doi:10.1158/1538-7445.AM2015-4519