Mechanistic PBPK/PD modeling of free and nano-liposomal irinotecan reveals formulation-specific determinants of disposition and efficacy

Irinotecan is widely used in cancer therapy but is limited by significant toxicities due to systemic and intestinal exposure to its active metabolite, SN-38. To improve its therapeutic profile, irinotecan has been encapsulated in pegylated liposome as a nano-liposomal form (nal-IRI) to modify its pharmacokinetics (PK) and enhance tumor delivery via the enhanced permeability and retention effect. While nal-IRI has shown clinical benefits, the formulation-specific PK and pharmacodynamics (PD) underlying its efficacy and safety remain unknown. This study aimed to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model to compare the disposition and tumor response of irinotecan and SN-38 following administration of free irinotecan (free-IRI, Camptosar®) and nal-IRI (Onivyde®) in pediatric tumor xenografts. Plasma and tissue PK data (liver, spleen, kidney, brain, lung, and tumor) were collected from healthy and tumor-bearing mice treated with various intravenous doses of both formulations. The model accurately described plasma, tissue, and tumor concentrations of irinotecan and SN-38. Key determinants of disposition included enterohepatic recycling, carboxylesterase-mediated conversion in liver/plasma, and clearance through biliary/metabolic pathways for irinotecan, and biliary/renal routes for SN-38. Nal-IRI exhibited formulation-specific characteristics, including phagocyte-mediated uptake, non-linear plasma clearance, liposomal release and permeability-limited tissue distribution, that are major determinants of nal-IRI disposition. PD modeling indicated intra-tumoral SN-38 exposure was the principal driver of antitumor efficacy. Nal-IRI achieved sustained and higher SN-38 tumor exposure, producing more rapid and durable tumor suppression than free-IRI. This integrated PBPK/PD framework provides mechanistic insights into the enhanced efficacy of nal-IRI and supports its optimized use in irinotecan-based cancer therapy.