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© 2002 American Society for Clinical Oncology
Irinotecan Dosing: Does the CPT in CPT-11 Stand for "Can’t Predict Toxicity"?Committee on Clinical Pharmacology, Cancer Research Center, The University of Chicago, Chicago, IL IRINOTECAN IS unique among the camptothecins because of its propensity to cause diarrhea, often of greater severity and clinical impact than its other major toxicity, myelosuppression. It was quickly recognized during irinotecan’s phase I trials that this would be a major issue in its development.1 Furthermore, the severity of the diarrhea was generally considered unpredictable and inconsistently correlated to interindividual pharmacokinetic variability.2 Clinical investigators learned to manage, but not prevent, the diarrhea during irinotecan’s phase II and III development.3,4 The drug was approved in France and Japan in 1995 and in the United States in 1996 for metastatic colorectal cancer, which was previously treated with fluorouracil. However, significant concerns about irinotecan’s toxicity have been expressed since regulatory approval, both in Japan and the United States.5,6 The recent uproar in the United States relates to the toxicity observed in cooperative group studies of irinotecan in combination with fluorouracil and leucovorin. This combination had been embraced as the standard regimen for metastatic colorectal cancer based on an apparent survival advantage in randomized clinical trials.7 However, the observed toxicity, including fatal adverse events, has lead to an abrupt change in perception regarding irinotecan and its role in colorectal cancer. One could argue that oncologists had become a bit cavalier about the drug and thus simply need to resume the same level of vigilance as was used in earlier clinical trials—with more aggressive supportive care and dose modifications for toxicity. Alternatively, one might argue that the dose should be reduced to prevent toxicity, although of course that raises the question of reducing efficacy. Others have suggested altering the schedule in an attempt to avoid the toxicity.6 And finally, the unspoken concern by some is that the drug is just too unpredictably toxic. To understand the toxicity of irinotecan, it is first necessary to become familiar with its complex clinical pharmacology. Irinotecan is a prodrug, requiring activation by carboxylesterases to SN-38, its active metabolite.8 SN-38 is detoxified by the polymorphic enzyme UGT1A1 to SN-38 glucuronide (SN-38G).9 The reverse reaction can also occur (by bacterial glucuronidases in the intestine) and may be modulated by changing the flora with antibiotics.10 Only a fraction of the administered irinotecan dose is converted to SN-38, with the remaining drug metabolized by CYP3A4 (and possibly CYP3A5) or excreted via hepatic or renal transport.11,12 A number of transporters are involved in the excretion of irinotecan and its metabolites, including MDR1 (P-glycoprotein), MRP2 (cMOAT), and BCRP.13,14 It is generally accepted that the late diarrhea ensuing from irinotecan administration is related to the direct effect of SN-38, irinotecan’s active metabolite, on the intestinal mucosa. We have previously suggested that variability in glucuronidation of SN-38 is the major determinant of the severity of diarrhea occurring on the weekly schedule of irinotecan.15 Recent studies have demonstrated that genetic variability at the UGT1A1 promoter correlates with both pharmacokinetics and toxicity.16,17 However, as discussed by Mathijssen et al,18 this is unlikely to be the sole factor. Nevertheless, it is reasonable to suggest that the UGT1A1 genotype is more relevant to irinotecan’s pharmacokinetics than body-surface area, which does not have a clinically meaningful correlation with any pharmacokinetic parameter. So, what should we do to maximize the therapeutic index of this important agent? First, we need to continue to study the pharmacodynamics of irinotecan. As noted above, late diarrhea seems to be due primarily to excreted SN-38 as modulated by its intraluminal formation from SN-38G (by bacterial glucuronidases). Most studies have suggested that myelosuppression is related to the plasma SN-38 area under the curve.2 But what about response? How important is intratumoral activation by carboxylesterases?19 Preclinical studies have demonstrated that transfection of potent carboxylesterases can enhance the cytotoxic effect.20 Is variability in response caused by variability in this hydrolytic pathway? Given that increased plasma SN-38 exposure seems to be associated with toxicity, might we want to maximize the ratio of plasma irinotecan to SN-38? If so, this has bearings on dose and schedule, as there may be saturation of plasma SN-38 formation at higher doses,21 which would favor the use of less frequent, higher dose schedules (eg, every 3 weeks). Can we identify patients prospectively who are at highest risk of toxicity or lowest chance of benefit? Given irinotecan’s complex clinical pharmacology, there are many hypotheses that can be tested regarding variability secondary to pharmacogenetics.22 This is a powerful approach once polymorphisms of potential clinical relevance have been identified, as genotyping is increasingly inexpensive, and assays can be performed on any tissue specimen (preferably normal tissue) collected at any time. We should obtain germline DNA samples (eg, single blood specimen or buccal swab) on all consenting patients in future clinical trials of irinotecan. Given the recent explosion in our understanding of genetic variability and its potential consequences, irinotecan is an excellent model for assessing the potential of pharmacogenetics to enhance the therapeutic index of drugs with a narrow therapeutic index. So what is the future of dosing of irinotecan and other cytotoxic agents? Is it dosing based on body-surface area or on genotyping, or is it one size fits all? The article by Mathijssen et al18 adds to our body of knowledge regarding the lack of importance of body-surface area for drug dosing in adults.23 So why do we keep doing it? Obviously, old habits die hard.24 But maybe the Food and Drug Administration, ostensibly a bastion of sanity, can set the standards in this regard. As they regulate all clinical trials of investigational agents, they could develop a policy regarding the use (and misuse) of body-surface area in oncology clinical trials. In this author’s opinion, body-surface area should not be used in any studies of investigational drugs, unless prior data exist that demonstrate a relationship to pharmacokinetics or toxicity. Once we rid ourselves of the misperception that we accurately individualize dosing with body-surface area, we will increase our likelihood of implementing the rewards of the Human Genome Project in the practice of oncology.25 ACKNOWLEDGMENTS Dr. Ratain is listed as an inventor on both pending and issued patents related to irinotecan; has received honoraria related to lectures on irinotecan; and consults for a number of companies in regard to both pharmacogenetics of anticancer agents and the development of camptothecin analogs. REFERENCES
1.
Rothenberg ML, Kuhn JG, Burris HA III, et al: Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11: 2194-2204, 1993 2. Gupta E, Ratain MJ: Camptothecin analogues: Topotecan and irinotecan, in Grochow LB, Ames M (eds): A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics. Baltimore, MD, Williams & Wilkins, 1998, pp 435-457 3. Bleiberg H, Cvitkovic E: Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: The European perspective. Eur J Cancer 32A: S18-S23, 1996
4.
Wadler S, Benson AB III, Engelking C, et al: Recommended guidelines for the treatment of chemotherapy-induced diarrhea. J Clin Oncol 16: 3169-3178, 1998 5. World Health Organization: Essential Drugs and Medicines Policy, Irinotecan: Warning and Precautions for Use, Japan, 1997. Http://www.who.int/medicines/library/pnewslet/pndec97.html 6. Sargent DJ, Niedzwiecki D, O’Connell MJ, et al: Recommendation for caution with irinotecan, fluorouracil, and leucovorin for colorectal cancer. N Engl J Med 345:144-145; discussion 146, 2001
7.
Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer: Irinotecan Study Group. N Engl J Med 343: 905-914, 2000
8.
Humerickhouse R, Lohrbach K, Li L, et al: Characterization of CPT-11 hydrolysis by human liver carboxylesterase isoforms hCE-1 and hCE-2. Cancer Res 60: 1189-1192, 2000 9. Iyer L, King CD, Whitington PF, et al: Genetic predisposition to the metabolism of irinotecan (CPT-11): Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101: 847-854, 1998[Medline]
10.
Kehrer DF, Sparreboom A, Verweij J, et al: Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7: 1136-1141, 2001
11.
Slatter JG, Schaaf LJ, Sams JP, et al: Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following I.V. infusion of [(14)C]CPT-11 in cancer patients. Drug Metab Dispos 28: 423-433, 2000
12.
Santos A, Zanetta S, Cresteil T, et al: Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans. Clin Cancer Res 6: 2012-2020, 2000
13.
Chu XY, Kato Y, Ueda K, et al: Biliary excretion mechanism of CPT-11 and its metabolites in humans: Involvement of primary active transporters. Cancer Res 58: 5137-5143, 1998 14. Schellens JH, Maliepaard M, Scheper RJ, et al: Transport of topoisomerase I inhibitors by the breast cancer resistance protein: Potential clinical implications. Ann N Y Acad Sci 922: 188-194, 2000[Medline]
15.
Gupta E, Lestingi TM, Mick R, et al: Metabolic fate of irinotecan in humans: Correlation of glucuronidation with diarrhea. Cancer Res 54: 3723-3725, 1994 16. Iyer I, Das S, Janisch L, et al: UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenom J (in press)
17.
Ando Y, Saka H, Asai G, et al: UGT1A1 genotypes and glucuronidation of SN-38, the active metabolite of irinotecan. Ann Oncol 9: 845-847, 1998
18.
Mathijssen RHJ, Verweij J, de Jonge MJA, et al: Impact of body-size measures on irinotecan clearance: Alternative dosing recommendations. J Clin Oncol 20: 81-87, 2002 19. Guichard S, Terret C, Hennebelle I, et al: CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues. Br J Cancer 80: 364-370, 1999[CrossRef][Medline]
20.
Wierdl M, Morton CL, Weeks JK, et al: Sensitization of human tumor cells to CPT-11 via adenoviral-mediated delivery of a rabbit liver carboxylesterase. Cancer Res 61: 5078-5082, 2001 21. Farabos C, Haaz MC, Gires P, et al: Hepatic extraction, metabolism, and biliary excretion of irinotecan in the isolated perfused rat liver. J Pharm Sci 90: 722-731, 2001[CrossRef][Medline]
22.
Innocenti F, Iyer L, Ratain MJ: Pharmacogenetics of anticancer agents: Lessons from amonafide and irinotecan. Drug Metab Dispos 29: 596-600, 2001 23. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19: 171-177, 2001[CrossRef][Medline] 24. Ratain MJ: Body-surface area as a basis for dosing of anticancer agents: Science, myth, or habit? J Clin Oncol 16: 2297-2298, 1998 (editorial)[Medline] 25. Ratain MJ, Relling MV: Gazing into a crystal ball: Cancer therapy in the post-genomic era. Nat Med 7: 283-285, 2001[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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