(W-002) Dual Physiologically-based Pharmacokinetics Models of Nano-Liposomal (Nal-IRI) and Non-Liposomal Irinotecan in Ewing’s Family Tumor Xenograft

Min Hee Kang, Pharm.D – Associate Vice President, Office of Research, Department of Medicine, Texas Tech University Health Sciences Center; Sukyung Woo, Ph.D – Associate Professor, Pharmaceutical Sciences, The State University of New York at Buffalo, School of Pharmacy & Pharmaceutical Sciences

Objectives: Nal-IRI is a nano-liposomal irinotecan approved for the management of metastatic colorectal cancer. The aim of this study is to characterize the disposition and biodistribution of irinotecan and SN-38 following Nal-IRI administration in Ewing’s Family tumor xenografts, and quantify the determinant factors of pharmacokinetics (PK) and the benefits of nanoparticle formulation Nal-IRI by developing a physiologically based pharmacokinetic (PBPK) model.

Methods: The PK data of CPT-11 and its metabolite SN-38 in plasma and various tissues (liver, spleen, kidney, brain, lung, tumor) were obtained following single intravenous doses of 5, 10, 20 mg/kg of Nal-IRI (5 mg/mL, nano-liposomal irinotecan) and irinotecan (Camptosar, 20 mg/mL, free drug formulation) in both non-tumor-bearing and tumor-bearing mice. A dual PBPK model for irinotecan and SN-38 was sequentially developed. Initially, the model described the disposition of the free drug formulation in non-tumor bearing mice, followed by the disposition of the nano-liposomal formation in tumor-bearing mice.

Results: The developed dual PBPK model well described the observed plasma and tissue PK profiles of both irinotecan and SN-38. Key features of the model for irinotecan and SN-38 disposition included biliary clearance and enterohepatic circulation of irinotecan and SN-38 in the liver, metabolic conversion of irinotecan to SN-38 by carboxylesterases in the liver and plasma, and renal clearance of SN-38. Specific components of the Nal-IRI formulation encompassed phagocytic uptake into the interstitial space of the liver, spleen, kidney, and lung, which exhibited linearity, alongside non-linear uptake in plasma; liposomal release of irinotecan, metabolic conversion in phagocytic cells, and liposomal stability in plasma. Global sensitivity analysis revealed that key parameters included plasma-tissue partition coefficients, biliary clearance, and metabolic clearance, all estimated with good precision. Significant elimination mechanisms included biliary clearance (0.999 mL/hr) and metabolic clearance (51.94 mL/hr) for irinotecan, while for SN-38, biliary clearance (6.31 mL/hr) and renal clearance (6.21 mL/hr) were notable. Critical parameters of the Nal-IRI PBPK model were associated with phagocytic cellular uptake, slow liposomal release kinetics, partition coefficient, and prolonged drug residence time in plasma and tissue, including tumors. The estimated value of the maximum Nal-IRI uptake rate by phagocytic cells was 13.6 mL/hr.

Conclusions: The quantification and characterization of drug disposition for both Nal-IRI and non-liposomal formulation irinotecan using a PBPK modeling approach suggest that phagocytic cellular uptake, prolonged drug residence time in tissues and plasma, and slow liposomal release kinetics are key aspects influencing the disposition and tissue distribution of nano-liposomal irinotecan.

Citations: [1] Kang MH, Wang J, Makena MR, et al. Activity of MM-398, nanoliposomal irinotecan (nal-IRI), in Ewing's family tumor xenografts is associated with high exposure of tumor to drug and high SLFN11 expression. Clin Cancer Res. 2015;21(5):1139-1150. doi:10.1158/1078-0432.CCR-14-1882