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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5331-5332 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.8644
The Value of Label Recommendations: How to Dose LapatinibClinical Pharmacokinetics Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC
Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, NC
Oncology Drug Discovery, GlaxoSmithKline, Philadelphia, PA
Clinical Development, GlaxoSmithKline, Philadelphia, PA To the Editor: A Commentary published July 16, 2007, by Drs Ratain and Cohen1 proposed that patients and prescribers could exploit the drug interaction by which food increases the bioavailability of lapatinib in order to decrease the dose, reducing the cost of treatment. We support the desire to find appropriate means of achieving more affordable health care, but we are concerned that the specific method proposed for lapatinib could have adverse consequences. Lapatinib (TYKERB, GlaxoSmithKline, Research Triangle Park, NC) is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2, a serious, life-threatening disease. As a molecular targeted therapy, achieving efficacy and avoiding toxicity requires maintaining optimal plasma concentrations. This demands careful consideration of the factors that influence pharmacokinetics. Patients, prescribers, and drug developers expect targeted therapies to deliver a clinical benefit with minimal toxicity, and all share the goal of keeping therapy on target. However, the suggestion to lower the administered dose by increasing lapatinib bioavailability with food will not achieve this goal. The authors question why the TYKERB label indicates dosing without food, and then speculate that the effect of food was unknown before conducting the pivotal efficacy trial, when in fact, it was known. The US Food and Drug Administration–approved label, instructing that lapatinib be dosed in the fasted state, was based on data obtained from three clinical studies conducted by the sponsor to characterize the food effect. The last of these studies2 was presented in a poster session at the American Society of Clinical Pharmacology and Therapeutics (ASCPT) March 2007 meeting, and is referenced in their commentary. The background on that poster included a brief description of the previous food-effect study results. Together, the three studies indicated that the effect of food on lapatinib bioavailability was (1) much larger than with most drugs, (2) increased disproportionately with the fat content of a meal, and (3) increased with increasing dose (Table 1).
These characteristics clearly indicate that decreasing the dose and using the contents of a meal to adjust bioavailability in order to achieve therapeutic plasma concentrations is not as simple as the majority of the commentary implies. The greater concern over dosing lapatinib with food at any dose is increased variability in systemic exposure. The data presented in March at the ASCPT meeting showed that this food effect was highly variable between individual patients. The commentary cites 48% inter-patient variability in apparent oral clearance. This translates to 68% variability in systemic exposure (area under the curve). However, these statistics do not fully convey the magnitude of variability experienced by individual patients in the study, which were strikingly different, ranging from a slight decrease to as much as a 24-fold increase. Patients participating in these controlled studies were required by the protocol to eat identical meals, but in the real world, patients eat differently from each other, and from day to day, sometimes being unable to eat at all. If these variations in eating habits were combined with the inherent variability observed in our controlled studies, the proposed cost savings could be accompanied by increased toxicity, or worse, disease progression if a loss of appetite interfered with maintaining a consistent food effect. If this interaction had been as modest and uncomplicated as it is with most other drugs, dosing lapatinib with food could have been considered as the authors suggest. However, based on the risk of potentially serious adverse effects secondary to this high interindividual variability, we concluded that the current recommendation to dose without food was the best way to reliably deliver consistent therapy. The Commentary also contained a suggestion that even greater cost savings might be achieved by drinking grapefruit juice with food to further boost bioavailability. This suggestion is particularly worrisome, because there is a large body of literature indicating that the effect of grapefruit juice is highly variable and can alter bioavailability in either direction due to multiple effects on metabolic enzymes and intestinal and hepatic drug transport proteins.3,4 More importantly, this would increase the risk of serious toxicity from other drugs prescribed concomitantly for these patients, such as calcium channel blockers5 and benzodiazepines.6 In addition to cost savings, a potential benefit was proposed in that dosing with food could increase absorption, leaving less unabsorbed drug in the gut, and thereby decrease diarrhea. Food certainly increases the bioavailability of lapatinib, but the data suggest that this is not solely due to increased absorption. In fact, the data presented at the ASCPT meeting suggested no decrease in the incidence or severity of diarrhea when lapatinib was administered with food (Table 2). Based on this clinical experience, the proposed benefit appears unlikely.
Near the end of their proposed off-label dosing regimen, the authors strongly recommend against implementing the proposal in practice. This is appropriate advice, given that they had not reviewed all of the data on which the dosing recommendation was based. Like many patients who, in response to the Commentary, called the sponsor to ask if dosing with food would improve efficacy, we are all seeking ways to improve their therapy. So we welcome the scientific debate and the public reaction that reminds us of our obligation to patients who look to us for guidance in their struggle with disease. We hope that this brief discussion of the data, underlying one of the many decisions made in the course of developing a new drug, is helpful to both patients and practitioners. Development of new drugs with complex pharmacokinetic properties is a challenge we continue to take on long after they become available to patients, as we continue to examine ways in which to make dosing easier. However, until a safer and more effective regimen is demonstrated to treat patients with this drug, the dosing instructions in the US Food and Drug Administration–approved label represent the best and most reliable method to deliver lapatinib therapy to patients with breast cancer. 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); Andrew P. Beelen, GlaxoSmithKline (C); Peter T.C. Ho, GlaxoSmithKline (C); Debasish F. Roychowdhury, GlaxoSmithKline (C) Consultant or Advisory Role: None Stock Ownership: Kevin M. Koch, GlaxoSmithKline; Andrew P. Beelen, GlaxoSmithKline; Peter T.C. Ho, GlaxoSmithKline; Debasish F. Roychowdhury, GlaxoSmithKline Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
REFERENCES
1. 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 2. Reddy N, Cohen R, Whitehead B, et al: A phase I, open-label, three-period, randomized crossover study to evaluate the effect of food on the pharmacokinetics of lapatinib in cancer patients. Clin Pharmacol Ther 81:S16-S17, 2007 3. Bailey DG, Malcolm J, Arnold O, et al: Grapefruit juice: drug interactions. Br J Clin Pharmacol 46(2):101-110, 1998 4. Bressler R: Grapefruit juice and drug interactions: Exploring mechanisms of this interaction and potential toxicity for certain drugs. Geriatrics 61:12-18, 2006[Medline] 5. Sica DA: Interaction of grapefruit juice and calcium-channel blockers. Am J Hypertension 19:768-773, 2006[CrossRef][Medline] 6. Veronese ML, Gillen LP, Burke JP, et al: Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice. J Clin Pharmacol 43:831-839, 2003
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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