Irinotecan and its active metabolite, SN‐38: review of bioanalytical methods and recent update from clinical pharmacology perspectives

Abstract

The introduction of irinotecan has revolutionized the applicability of camptothecins as predominant topoisomerase I inhibitor for anti-cancer therapy. The potent anti-tumor activity of irinotecan is due to rapid formation of an in vivo active metabolite, SN-38. Therefore, irinotecan is considered as a pro-drug to generate SN-38. Over the past decade, side-by-side with the clinical advancement of the use of irinotecan in the oncology field, a plethora of bioanalytical methods have been published to quantify irinotecan, SN-38 and other metabolites. Because of the availability of HPLC, LC-MS and LC-MS/MS methods, the pharmacokinetic profiling of irinotecan and its metabolites has been accomplished in multiple species, including cancer patients. The developed assays continue to find use in the optimization of newly designed delivery systems with regard to pharmacokinetics to promote safe and effective use of either irinotecan or SN-38. This review intends to: firstly, provide an exhaustive compilation of the published assays for irinotecan, SN-38 and other metabolite(s) of irinotecan, as applicable; secondly, to enumerate the validation parameters and applicable conclusions; and thirdly, provide some recent perspectives in the clinical pharmacology arena pertaining to efflux transporters, pediatric profiling, role of kidney function in defining toxicity, drug-drug interaction potential of irinotecan, etc.

Effects of neoadjuvant chemotherapy on patients with primary vaginal squamous cell carcinoma

“…Irinotecan is a topoisomerase Ⅰ inhibitor, specifically acting on the S phase of the cell cycle by impeding DNA synthesis and inhibiting the growth of tumor cells (20). Irinotecan is currently widely applied in the treatment of colorectal, lung, esophageal, cervical and ovarian cancer, as well as other tumors, with good therapeutic outcomes.…”

Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study

“…[28][29][30][31] However, our findings in this trial illustrate the potential caveats of early pharmacological evaluation of investigational new drugs, stressing the need to systematically question the relevance of analytical data.…”

The Hidden Ingredients Affecting Cancer Patients Outcome and the Mathematical Journey to Their Uncover

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Since the identification of Nitrogen mustard as a non-specific DNA alkylating agent and its clinical assessment by Gilman and Goodman at Yale University in 1942 for Lymphoma treatment [1], the field of medical oncology has rapidly expanded.It relies on understanding and exploring numerous factors affecting cancer patient's outcome, including: 1) Familiarity with the natural history of various malignancies [2] and understanding the significant of patients' well-being as predictor to survive and tolerate therapy, scored as the "Performance Status" [3,4];2) Basic biology events of normal cycling cells [5], and principals involved in cancer pathogenesis named "hallmarks of cancer," including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, angiogenesis, activating invasion and metastasis, and recently expanded to include also reprogramming of energy metabolism and evading immune destruction [6,7]; 3) Identification of tumor features or biomarkers for tailored treatment approach including: "targeted" therapy (i.e., estrogen receptor expression for hormonal manipulations in breast cancer [8]; Her2 overexpression for anti-Her2 agents in breast and gastric tumors [9]), mutations affecting up/down stream biological events, and identifying patients who will not benefit from blocking single protein in a chain process (i.e., RAS mutation signaling lack of benefit from anti-EGFR directed monoclonal therapy in colorectal tumors [10]), and those of unique molecular/genetic conditions signaling tumors prone to specific therapy (i.e., BRCA1/2 mutations and benefit of PARP inhibitors [11]);4) The role of tumor stroma and its interaction with cancer and anticancer drugs [12,13]; 5) Pharmacological factors such as those affecting drug absorption and delivery, metabolic production and elimination of active agents from their pro-drugs (i.e., SN-38 production from Irinotecan infusion [14]), and the effect of genetic heterogeneity in metabolizing enzymes, concomitant medications use [15], and liver and kidney function on active drug bio-availability; 6) And above all, the proof of efficacy and safety of tested drugs in well conducted clinical trials with specified clinical outcome [16].While understanding of each of those factors contributes to the emerging progress in medical oncology, many research and clinical publications focus on only few factors, mostly on those related to a specific new drug or a matched biologic process. Indeed, in real life and post-marketing world, many additional drug/tumor/co-morbidity/ ethnic and geographic factors/social status/economic status/insurance coverage and educational factors, contribute to patient ability to access and benefit from anti-cancer care.

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“…4) The role of tumor stroma and its interaction with cancer and anticancer drugs [12,13]; 5) Pharmacological factors such as those affecting drug absorption and delivery, metabolic production and elimination of active agents from their pro-drugs (i.e., SN-38 production from Irinotecan infusion [14]), and the effect of genetic heterogeneity in metabolizing enzymes, concomitant medications use [15], and liver and kidney function on active drug bio-availability; 6) And above all, the proof of efficacy and safety of tested drugs in well conducted clinical trials with specified clinical outcome [16].…”