Abstract 1369: Predicting clinical pharmacokinetics and toxicity of current and emerging oncology therapeutics by normothermic perfusion of isolated human-sized organs

Abstract

Abstract Novel cancer therapeutics have less than a 12% probability of translating from bench to bedside. Unwarranted toxicity and inadequate therapeutic delivery due to uptake by clearance organs, not predicted by current preclinical methods, have contributed towards this high rate of attrition. In the present work, we propose normothermic machine perfusion of human or human-sized organs as a more predictive, closer-to-human model to investigate drug pharmacokinetics and toxicity. Over the past decade, developments in the field of organ preservation for transplantation have enabled prolonged (>12 hours) normothermic machine perfusion (NMP) of isolated porcine or human organs ex vivo, maintaining quasi-physiological haemodynamic, synthetic and metabolic function using a packed red cell perfusate with physiological oxygenation and nutrient levels at normal body temperature. This preserves physiological processes such as metabolism and drug elimination, and enables easy access to tissue, blood and excreted biological fluids, with NMP livers producing bile and NMP kidneys producing urine. We hypothesise that this will provide a physiologically relevant platform to investigate drug pharmacokinetics and toxicity. We selected a widely used small-molecule chemotherapeutic (Irinotecan hydrochloride 2mg/ml, Medac, UK) which has seen decades of clinical use and benefits from extensive clinical pharmacokinetic data. The small-molecule drug was infused into isolated porcine and human livers and kidneys, with quantification of concentration time profiles of the prodrug and its main metabolites in plasma, bile and urine over 16-24 hours of NMP. In addition to irinotecan (CPT11), three of its metabolites (APC, SN38G, SN38) were successfully detected and quantified, demonstrating peak plasma concentrations (Cmax ~ 10,000 ng/mL, 1000 ng/mL, 100 ng/g, 30 ng/g), plasma decay rates and percentages of injected dose in bile (%ID ~20%, 8%, 25%, 1%) and urine (%ID ~20%, 0.06%, 0.5%,0.1%) that are comparable to clinical data. Drug-tissue toxicity could also be adequately replicated in the NMP model. In conclusion, we have demonstrated that human-sized isolated, normothermically perfused livers and kidneys accurately represent the clinically observed pharmacokinetic and toxicity profiles of an established small-molecule therapeutic. Further model validation is ongoing for biologics and other nanomedicines which are susceptible to clearance by the mononuclear phagocytic system or are hepato- or nephrotoxic. If this proves successful, normothermic machine perfusion of isolated porcine and human organs could greatly aid the early screening of candidate therapeutics and significantly enhance the pace and success rate with which they are translated into patients. Citation Format: Tamsyn Clark, Luca Bau, Fungai Dengu, Daniel Voyce, Robert Carlisle, Peter Friend, Constantin Coussios. Predicting clinical pharmacokinetics and toxicity of current and emerging oncology therapeutics by normothermic perfusion of isolated human-sized organs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1369.