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Originally published as JCO Early Release 10.1200/JCO.2009.23.9186 on July 6 2009 © 2009 American Society of Clinical Oncology.
Reply to I.F. TannockClinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC
Myriad Pharmaceuticals, Salt Lake City, UT
Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH In reply to Dr Tannock's1 comments on our paper,2 we would like to provide some context for our conclusion on how to administer lapatinib in relation to food, which he believes is wrong. Our conclusion was based on our understanding of pharmacokinetic and therapeutic variability, well before it was possible to express a particular bias in relation to the cost of lapatinib therapy. He and other commentators3,4 have focused on inter–individual variability, which is relevant to achieving consistent treatment between patients. The observation that, in relative terms, inter–individual variability was similar between the fasted state (68%) and fed state (52%) seems to reassure them. But this should be of concern, because the observation that inter–individual variability did not decrease significantly with the large increase in the mean effect of food indicates that the effects we observed were not approaching the limit of maximum or 100% bioavailability. Without this inherent limit, the effect of food reported in our study of 27 patients could be exceeded with similar relative and greater absolute variability in other patients. Indeed, the outlier mentioned by Dr Tannock, one of 27, may represent a sizeable subgroup of patients. He proposes a dose adjustment by inferring that lapatinib pharmacokinetics are linear, based on the behavior of its half-life, which he erroneously presumes to reflect only drug elimination. He then compounds this error in assuming that linear elimination implies linear absorption. It should be evident that the effects of food on lapatinib bioavailability do not reflect linear processes when a meal containing 2 g of fat elicits a three-fold average increase in the area under the concentration-time curve (AUC), while a meal containing 52 g of fat elicits a four-fold average increase in AUC. Let us hope that this explanation is helpful to others in avoiding the mistake of applying simple math to lapatinib pharmacokinetics. However, our conclusion, and that of the regulatory agencies who reviewed these data,5 was that the more important aspect of variability, to which Dr Tannock1 and others have not given sufficient thought or debate, is intra–individual variability.6 This is perhaps to be expected with the relatively recent emergence of a need for oncology practitioners to understand the nuances of oral chemotherapy in patients with cancer. Thus, although breakfast may be arguably the most consistent meal of the day, it is by no means identical from 1 day to the next for most individuals, and perhaps less so for patients with cancer. Hence, the likelihood that a patient would eat a low-fat breakfast one day and skip breakfast the next would result in the kind of variability that should concern oncologists. Advising patients to dose lapatinib with food is likely to result in three-fold or larger differences in systemic exposure from 1 day to the next, certainly not a rational goal for optimal therapy. Dr Tannock1 also raises questions about our objectivity and the editor's decision to publish our article because the authors are either employed by or conduct research funded by a for-profit pharmaceutical company, and because our conclusions differ from his. The data generated by scientists and clinical investigators for the highly regulated pharmaceutical industry is subjected to far greater scrutiny by regulatory agencies around the world than is the data generated independently by academic investigators. Journal of Clinical Oncology's policy of disclosure for possible conflicts is in everyone's interest, even though it cannot account for all sources of potential bias. In our opinion, scientific research should and can best be judged on the merits of the data, and the scientists who work to produce that data deserve the presumption of integrity unless proven otherwise. We believe the primary objective of scientific literature and correspondence should be to progress science by objective discourse and respectful debate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Kevin M. Koch, GlaxoSmithKline (C) Consultant or Advisory Role: Lionel D. Lewis, GlaxoSmithKline (C) Stock Ownership: Kevin M. Koch, GlaxoSmithKline Honoraria: None Research Funding: Lionel D. Lewis, GlaxoSmithKline Expert Testimony: None Other Remuneration: None REFERENCES
1. Tannock IF: Effects of food on bioavailability of lapatinib: Useful data, wrong conclusion. J Clin Oncol 27:e42; 2009. 2. Koch KM, Reddy NJ, Cohen RB, et al: Effects of food on the relative bioavailability of lapatinib in cancer patients. J Clin Oncol 27:1191–1196, 2009. 3. Ratain MJ, Cohen EE: The value meal: How to save $1,700 per month or more on lapatinib. J Clin Oncol 25:3397–3398, 2007. 4. Ratain MJ, Cohen EE: In reply. J Clin Oncol 25:5334–5335, 2007. 5. Rahman A, Pazdur R, Wang Y, et al: The value meal: Effect of food on lapatinib bioavailability. J Clin Oncol 25:5333–5334, 2007. 6. Koch KM, Beelen AP, Ho PTC, et al: The value of label recommendations: How to dose lapatinib. J Clin Oncol 25:5331–5332, 2007.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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