Journal of the National Cancer Institute Advance Access originally published online on January 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(3):225; doi:10.1093/jnci/djm303
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© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
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Affiliation of authors: Division of Pharmacotherapy and Experimental Therapeutics and the Lineberger Comprehensive Cancer Center, UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC
Correspondence to: Howard L. McLeod, PharmD, UNC Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, Campus Box 7360, Kerr Hall, Chapel Hill, 27599-7360 NC (e-mail: hmcleod{at}unc.edu).
We thank Dr Ichikawa and colleagues for their kind comments. Their preliminary irinotecan pharmacokinetic data from Japanese cancer patients with low-activity UGT1A1 genotypes who participated in an irinotecan dose escalation study provide some additional support for the findings of our study (1). The ratios of the areas under the concentration time curves of SN-38 to SN-38G for three of the four patients appear to increase with increasing dose of irinotecan. This observation, although based on few patients, indicates that the extent of SN-38 glucuronidation decreased with increasing irinotecan dose. We look forward to seeing the results on completion of their study.
On the basis of the findings of a few initial studies, the US Food and Drug Administration (FDA) made the recommendation that patients with the UGT1A1*28/*28 genotype should receive a lower starting dose of irinotecan, and the package insert of the drug was amended accordingly (1,2) in the interest of patient safety. Our findings indicate that, for UGT1A1*28/*28 patients, UGT1A1*28 genotype–based dosing of irinotecan is likely to improve patient safety if they are being treated with high doses of irinotecan (>250 mg/m2) but not if they are being treated with low doses (<150 mg/m2). Therefore, genotype-based dosing may not be necessary for all patients (1). Our findings also indicate that the current recommendations for irinotecan dosing may be too broad and so the irinotecan package label should be fine tuned to acknowledge the effect of irinotecan dose on the association between UGT1A1*28 genotype and hematologic toxicity. Many media outlets reported our findings with bold titles that implied an FDA error. Rather, we view FDA pharmacogenetic label updates as an iterative process in which refinement of the prescribing information is performed at intervals dictated by the robustness of the new data.
REFERENCES
1. Hoskins JM, Goldberg RM, Qu P, Ibrahim JG, McLeod HL. UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. J Natl Cancer Inst (2007) 99(17):1290–1295.
2. Haga SB, Thummel KE, Burke W. Adding pharmacogenetics information to drug labels: lessons learned. Pharmacogenet Genomics (2006) 16(12):847–854.[Web of Science][Medline]
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J Natl Cancer Inst 2008 100: 224-225.
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