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Journal of Clinical Oncology, Vol 25, No 33 (November 20), 2007: pp. 5333-5334 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.6381
The Value Meal: Effect of Food on Lapatinib BioavailabilityOffice of Clinical Pharmacology, Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD To the Editor: The Ratain and Cohen commentary1 suggests that, based on a pharmacokinetic study and predicted exposure, lapatinib may be taken with food to reduce dose and drug expenditures. The authors also suggest that such a maneuver may potentially reduce the incidence of diarrhea, which is considered a major toxicity in lapatinib treatment. The US Food and Drug Administration (FDA) cautions against the use of a reduced lapatinib dose taken with a meal because it may potentially compromise the treatment benefit of an effective therapy for advanced or metastatic breast cancer. US FDA approves drugs based on the evaluation of its benefits and risks in the indicated patient population (under the conditions defined in clinical trials submitted in a New Drug Application for the drug's approval).2 Any subsequent alterations in the dose, schedule, and conditions of use are carefully evaluated to determine if the changes are adequately supported by clinical data and do not compromise with the safety or effectiveness of the therapy that led to the drug's approval. Although a pharmacokinetic study3 suggests that the lapatinib exposure is significantly increased when taken with a high-fat meal (compared with a fasted state), the exposure from a lower dose of lapatinib (500 mg) taken with a meal compared to the 1,250-mg dose taken 1 hour before or after meals is not known. Further clinical studies including a relative bioavailability study evaluating lower lapatinib dose taken with a meal versus a 1,250-mg dose taken without a meal will be required for changing any dosing recommendation in the drug label. Therefore, any practical considerations to lower lapatinib dose taken with a meal to reduce drug cost should be carefully evaluated before deviating from the recommended dosing.2 These considerations include inter- and intrapatient variability in bioavailability, dietary effects on concomitant medications, and differing patterns of oral intake and food constituents. Individual food intake varies from time to time. Concomitant medications and chemotherapy-induced nausea, vomiting, and diarrhea may lead to erratic food intake,4 preventing some patients from ingesting a high-fat, high-calorie meal or a standard meal consistently for the 14 days of lapatinib treatment cycle. The meal's composition (caloric intake and fat, protein, and carbohydrate content) may have unpredictable effects on gastric emptying and intestinal motility in a given individual. The average increase in lapatinib's bioavailability with a low-fat and a high-fat meal has been demonstrated in preapproval clinical studies, suggesting that individual patients taking the recommended dose with food will have variable (52% coefficient of variability) and unpredictable changes in absorption. The lapitinib food-effect study shows that area under the curve ratios (fed/fasted ratio) in some individuals could be less than one, while others could have as high as 24-fold increased exposure when provided with a high-fat meal. Manipulation of dose, based on mean exposure value from the food-effect study, will result in individual patients being potentially under- or overexposed from the mean-adjusted dose of lapatinib. Ratain and Cohen indicated that "using a lower dose with food would markedly reduce the amount of unabsorbed drug, and, therefore, theoretically also reduce the frequency and/or severity of diarrhea." However, this is hypothetical, because the preapproval clinical food effect study disclosed that the tolerability was similar for patients taking 1,500-mg dose with or without a meal. The authors indicated that "we should view drug-drug and drug-food interactions as opportunities to lower costs." Drug sparing through drug interactions is not a new concept, but they need to be explored thoroughly before including these data in labels. US FDA has approved products that are concomitantly administered with an enzyme inhibitor to increase systemic exposure. Ritonavir, administered at a fixed dose, has been used to increase the bioavailability of both lopinavir5 and tipranavir.6 In the registration trials, rinotavir was incorporated with the tested drugs to establish the safety and effectiveness of the drugs in combination. Unlike manipulation of dose by food content, the ritonavir dose is constant, and its effects on the bioavailability of lopinavir and tipranavir have been show to be reliable and consistent. Grapefruit juice's use as a "drug-sparing agent" has not been thoroughly investigated, although it can theoretically increase systemic exposure of drugs through enzyme and/or efflux inhibition. These effects are dependent on the juice's volume, brand, and even the type of grapefruit and methods used to prepare the juice. Drug dosing and resulting drug exposure, especially for the treatment of advanced cancer, is finely balanced to provide optimal benefit with acceptable risks. Dietary manipulations that are inconsistent in their effects on drug exposure should be avoided in clinical use, since the clinical benefit of such a maneuver is not known and potentially can harm the patients by compromising that drug's effectiveness or toxicity.7,8 The US FDA cautions against the lowering of lapatinib dose when taken with a meal to manipulate systemic drug exposure as a therapeutic maneuver to reduce the number of tablets consumed and drug expenditures. Such an action may compromise the effectiveness and safety of the therapy, which would not represent value to patients. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. 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. Tykerb Label. http://www.fda.gov/cder/foi/label/2007/022059s001lbl.pdf 3. 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 4. Women Fitness: Nutrition of the Cancer Patients. http://www.womenfitness.net/programs/nutrition/nutrition.htm 5. Invirase Label. http://www.fda.gov/cder/foi/label/2007/020628s025,021785s004lbl.pdf 6. Kaletra Label. http://www.fda.gov/cder/foi/label/2007/021251s016,021906s005lbl.pdf 7. Huang S-M, Temple R, Throckmorton DD, et al: Drug-drug interactions: Study design, data analysis and implications for dosing recommendations, Clin Pharmacol Ther 81:298-304, 2007[CrossRef][Medline] 8. Huang S-M, Temple R, Lesko LJ: Drug-Drug, drug-dietary supplement, and drug-citrus fruit and other food interactions—labeling implications, in Lam F, Huang S-M, Hall SD (eds): Herbal Supplements–Drug Interactions. New York, NY, Informa Healthcare, 2006
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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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