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 reported in the phase III NAPOLI-1 trial in metastatic PDAC following failure of gemcitabine-based therapy. Several features of nal-IRI pharmacokinetics (PK) could result in better outcomes versus nonliposomal 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 could influence enhanced localized irinotecan activity and toxicity. Liposomal irinotecan exploits the enhanced permeability and retention effect in cancer, accumulating in tumor tissues. Liposomal irinotecan also has a longer half-life and higher area under the concentration-time curve (0-∞) than nonliposomal 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 nal-IRI is no worse than nonliposomal irinotecan. Liposomal irinotecan exemplifies how liposomal encapsulation of a chemotherapeutic agent can alter its PK properties, improving clinical outcomes for patients. Liposomal irinotecan is currently under investigation in other malignancies including biliary tract cancer (amongst other gastrointestinal cancers), brain tumors, and small-cell lung cancer.

Since its clinical introduction in 1998, the topoisomerase I inhibitor irinotecan has been widely used in the treatment of solid tumors, including colorectal, pancreatic, and lung cancer. Irinotecan therapy is characterized by several dose-limiting toxicities and large interindividual pharmacokinetic variability. Irinotecan has a highly complex metabolism, including hydrolyzation by carboxylesterases to its active metabolite SN-38, which is 100- to 1000-fold more active compared with irinotecan itself. Several phase I and II enzymes, including cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A, are involved in the formation of inactive metabolites, making its metabolism prone to environmental and genetic influences. Genetic variants in the DNA of these enzymes and transporters could predict a part of the drug-related toxicity and efficacy of treatment, which has been shown in retrospective and prospective trials and meta-analyses. Patient characteristics, lifestyle and comedication also influence irinotecan pharmacokinetics. Other factors, including dietary restriction, are currently being studied. Meanwhile, a more tailored approach to prevent excessive toxicity and optimize efficacy is warranted. This review provides an updated overview on today's literature on irinotecan pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Twenty-five years ago, the cytotoxic drug irinotecan (IRT) was first approved in Japan for the treatment of cancer. For more than two decades, the IRT prodrug has largely contributed to the treatment of solid tumors worldwide. Nowadays, this camptothecin derivative targeting topoisomerase 1 remains largely used in combination regimen, like FOLFIRI and FOLFIRINOX, to treat metastatic or advanced solid tumors, such as colon, gastric and pancreatic cancers and others. This review highlights recent discoveries in the field of IRT and its derivatives, including analogues of the active metabolite SN38 (such as FL118), the recently approved liposomal form Nal-IRI and SN38-based immuno-conjugates currently in development (such as sacituzumab govitecan). New information about the IRT mechanism of action are presented, including the discovery of a new protein target, the single-stranded DNA-binding protein FUBP1. Significant progress has been made also to better understand and manage the main limiting toxicities of IRT, chiefly neutropenia and diarrhea. The role of drug-induced inflammation and dysbiosis is underlined and strategies to limit the intestinal toxicity of IRT are discussed (use of β-glucuronidase inhibitors, plant extracts, probiotics). The detailed knowledge of the metabolism of IRT has enabled the identification of potential biomarkers to guide patient selection and to limit drug-induced toxicities, but no robust IRT-specific therapeutic biomarker has been approved yet. IRT is a versatile chemotherapeutic agent which combines well with a variety of anticancer drugs. It offers a large range of drug combinations with cytotoxic agents, targeted products and immuno-active biotherapeutics, to treat a variety of advanced solid carcinoma, sarcoma and cancers with progressive central nervous system diseases. A quarter of century after its first launch, IRT remains an essential anticancer drug, largely prescribed, useful to many patients and scientifically inspiring.

Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan's molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells' resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.