An_2026_Int.J.Pharm__126671

Irinotecan is widely used in cancer therapy but is limited by significant toxicities due to systemic and intestinal exposure to its active metabolite, SN38. 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(a)) and nal-IRI (Onivyde(a)) 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, nonlinear 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.