Pharmacokinetics of Irinotecan and Its Metabolites

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.99.190 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12454126 Pharmacokinetics of Irinotecan and Its Metabolites Jim SiderovxJim SiderovSearch for articles by this author Ron H.J. MathijssenxRon H.J. MathijssenSearch for articles by this author , Walter J. LoosxWalter J. LoosSearch for articles by this author , Alex SparreboomxAlex SparreboomSearch for articles by this author , Jaap VerweijxJaap VerweijSearch for articles by this author , Mats O. KarlssonxMats O. KarlssonSearch for articles by this author Show More Austin & Repatriation Medical Centre, Heidelberg, Victoria, AustraliaErasmus MC–Daniel den Hoed Cancer Center, Rotterdam, the Netherlands, Uppsala University, Uppsala, Sweden https://doi.org/10.1200/JCO.2002.99.190 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01122002In Reply:We thank Dr Siderov for his comments on our article.1 We share his concern that the topic of photodegradation of anticancer drugs has been seriously underrated in oncology, despite the possible clinical implications. In the case of irinotecan, however, this matter has been studied extensively and the overall clinical impact seems to be very limited.According to a recent textbook,2 aqueous solutions of both 5% dextrose or 0.9% sodium chloride can be used for administration of irinotecan hydrochloride. These mixtures are physically and chemically stable for up to 24 hours at room temperature when exposed to ambient fluorescent light.2 When kept refrigerated and protected from light, they remain stable for 48 hours. Nonetheless, refrigeration is not recommended because of occasional visible precipitation.2 It is common practice in our hospital to prepare the chemotherapy immediately before (within 1 to 2 hours) the actual drug infusion. In addition, the point raised by Dr Siderov, that a pH value of more than 6.5 results in 10% loss of drug within 3 hours, is only problematic when the irinotecan preparation is directly combined with other drugs, such as methylprednisolone.2 Without such combined drug preparation, the pH value remains much lower (since sodium chloride has no buffer capacity), and hence the issue is less relevant. Furthermore, as a result of the low pH value of this solution, the active lactone form of irinotecan predominates instead of the inactive carboxylate form.Despite these misunderstandings, photodegradation can be a huge problem clinically for a number of structurally related chemotherapy drugs. This is exemplified by the recent observation that photodegradation of lurtotecan leads to formation of a product that is two- to 18-fold more cytotoxic than the parent molecule, topotecan, and the irinotecan metabolite, SN-38.3 In contrast to the photodegradation of lurtotecan, photolysis of irinotecan occurs only at the fragile lactone-ring structure.4,5 In general, such degradation products are likely of subordinate (clinical) interest, because the reactivity of an intact lactone-ring structure is required for the generation of topoisomerase I–mediated DNA cleavage and antitumor activity of all known camptothecin analogs.6 1. Xie R, Mathijssen RHJ, Sparreboom A, et al: Clinical pharmacokinetics of irinotecan and its metabolites: A population analysis. J Clin Oncol 20:: 3293,2002-3301, Link, Google Scholar2. Trissel LA: Handbook on Injectable Drugs, ed 11 . Bethesda, MD, American Society of Health-Systems Pharmacists, 2001 Google Scholar3. Loos WJ, Verweij J, Kehrer DFS, et al: Structural identification and biological activity of 7-methyl-10,11-ethylenedioxy-20()-camptothecin, a photodegradant of lurtotecan. Clin Cancer Res 8:: 856,2002-862, S Medline, Google Scholar4. Dodds HM, Craik DJ, Rivory LP: Photodegradation of irinotecan (CPT-11) in aqueous solutions: Identification of fluorescent products and influence of solution composition. J Pharm Sci 86:: 1410,1997-1416, Crossref, Medline, Google Scholar5. Dodds HM, Robert J, Rivory LP: The detection of photodegradation products of irinotecan (CPT-11, Campto, Camptosar), in clinical studies, using high-performance liquid chromatography/atmospheric pressure chemical ionisation/mass spectrometry. J Pharm Biomed Anal 17:: 785,1998-792, Crossref, Medline, Google Scholar6. Chourpa I, Riou JF, Millot JM, et al: Modulation in kinetics of lactone ring hydrolysis of camptothecins upon interaction with topoisomerase I cleavage sites on DNA. Biochemistry 37:: 7284,1998-7291, Crossref, Medline, Google Scholar