Liposomal irinotecan (Onivyde): Exemplifying the benefits of nanotherapeutic drugs

Irinotecan is a topoisomerase inhibitor, widely used in treatment of malignancies including pancreatic ductal adenocarcinoma (PDAC) as part of the FOLFIRINOX regimen prescribed as a first-line treatment in several countries. However, irinotecan has not been successfully introduced as a second-line treatment for pancreatic cancer and few randomized clinical studies have evaluated its added value. Efficacy of liposomal irinotecan (nal-IRI) combined with 5-fluorouracil and leucovorin (5-FU/LV) was demonstrated in the phase III NAPOLI-1 trial in metastatic pancreatic ductal adenocarcinoma following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) may result in better outcomes vs non-liposomal irinotecan. Irinotecan is a prodrug that is converted to active SN-38 by carboxylesterase enzymes and inactivated by cytochrome P450 3A4/3A5. SN-38 is inactivated by UGT1A1 enzymes. Individual variations in their expression and activity may influence enhanced localized irinotecan activity and toxicity. nal-IRI exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. nal-IRI also has a longer half-life and higher area under the concentration-time curve (0–∞) than non-liposomal irinotecan, as the liposomal formulation protects cargo from premature metabolism in the plasma. This results in irinotecan activation in tumor tissue, leading to enhanced cytotoxicity. Importantly, despite the longer exposure, overall toxicity for liposomal irinotecan is no worse than non-liposomal irinotecan. nal-IRI exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. nal-IRI is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors and small-cell lung cancer.