Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide

Klein, Colin; Gupta, Elora; Reid, Joel M.; Atherton, Pamela J.; Sloan, Jeff A.; Pitot, Henry C.; Ratain, Mark J.; Kastrissios, Helen

doi:10.1067/mcp.2002.129502

Cited by 70 publications

(59 citation statements)

References 24 publications

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“…As a result of the uncoiling, topoisomerase I causes single-strand DNA breaks which are transient and easily repaired. Irinotecan, by blocking topoisomerase I, stabilizes the breaks within DNA, causing DNA fragmentation and ultimately cell death [Klein et al 2002;Douillard et al 2000;Saltz et al 2000]. Irinotecan is metabolized by hepatic carboxylesterases to its active compound, SN-38, and is inactivated through uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) [Klein et al 2002].…”

Section: Irinotecanmentioning

confidence: 99%

“…Irinotecan, by blocking topoisomerase I, stabilizes the breaks within DNA, causing DNA fragmentation and ultimately cell death [Klein et al 2002;Douillard et al 2000;Saltz et al 2000]. Irinotecan is metabolized by hepatic carboxylesterases to its active compound, SN-38, and is inactivated through uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) [Klein et al 2002]. Irinotecan as a single agent and second line to 5-FU-leucovorin improved survival by 2-3 months in patients with advanced colorectal cancer [Douillard et al 2000;Saltz et al 2000;Rougier et al 1998].…”

Section: Irinotecanmentioning

confidence: 99%

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Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor

Carethers

2008

Therap Adv Gastroenterol

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Colorectal cancer is a prevalent disease in Western countries. While prevention through screening is the best approach to combat the development of colorectal cancer through the removal of precursor adenomas, many patients present with advanced disease that will require surgery and systemic therapy to improve survival. With reference to systemic therapy, the median survival of patients with metastatic colorectal cancer (those with tumor spread to lymph nodes or distant sites) has improved over the past three decades due to the introduction of 5-fluorouracil (5-FU), its subsequent biomodulation, and the addition other chemotherapeutic agents. There is now evidence that the biology of the colorectal tumor, in addition to the stage of colorectal cancer, may predict response to 5-FU-based therapy. More recently, systemic biological therapies that target signaling processes for tumor growth, such as epidermal growth factor receptor, and vascular endothelial growth factor, are also effective in improving patient survival with metastatic colorectal cancer. The use of a combination of systemic therapies that include chemotherapy and biologic therapy should continue to increase patient survival with metastatic colorectal cancer through appropriately designed clinical trials. Treatments based on the biology of the colorectal tumor also need to be examined through clinical trials.

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Section: Irinotecanmentioning

confidence: 99%

Section: Irinotecanmentioning

confidence: 99%

Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor

Carethers

2008

Therap Adv Gastroenterol

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“…The method should combine the fitted parameters such that the resulting combinations relate to different aspects or pathways in the drug's pharmacokinetics. We chose to examine irinotecan, since considerable information already existed about its pharmacokinetics (20,21) and pharmacogenetics. (22) We expected the analysis to highlight certain known pharmacogenetics relationships, while also providing some leads or insights into other as yet unknown relationships.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetic Pathway Analysis of Irinotecan

Rosner

Panetta

Innocenti

et al. 2008

Clin Pharmacol Ther

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Irinotecan, a chemotherapeutic agent for various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics allows for potentially many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fit a seven-compartment pharmacokinetic model with enterohepatic recirculation to concentrations of irinotecan and metabolites SN-38, SN-38G (glucuronide), and APC. Principal component analysis (PCA) of patientspecific parameter estimates produced measures interpretable along pathways. Nine principal components characterized overall variation well. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and SN-38G's elimination. The component characterizing irinotecan's compartments was associated with HNF1α and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis identified known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

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“…In the model, age and bilirubin levels (pretreatment) served as co-variates (Thompson et al, 2008). While the developed model was shown to have striking similarity when compared with the adult population pharmacokinetic model that was previously reported for irinotecan (Klein et al, 2002), it also independently confi rmed that co-variates of age and bilirubin were important to predict toxicity of irinotecan (Thompson et al, 2008). The pediatric model unambiguously supported the current daily dosing schedule used for irinotecan in pediatric patients (Thompson et al, 2008).…”

Section: System: Lc-ms/msmentioning

confidence: 78%

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

Mullangi

Ahlawat²,

Srinivas³

2009

Biomedical Chromatography

154

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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.

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Population pharmacokinetic model for irinotecan and two of its metabolites, SN-38 and SN-38 glucuronide

Cited by 70 publications

References 24 publications

Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor

Review: Systemic treatment of advanced colorectal cancer: Tailoring therapy to the tumor

Pharmacogenetic Pathway Analysis of Irinotecan

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

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