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Originally published as JCO Early Release 10.1200/JCO.2007.12.0758 on July 16 2007 © 2007 American Society of Clinical Oncology.
The Value Meal: How to Save $1,700 Per Month or More on Lapatinib
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL Drug labels (ie, package inserts) must be approved by national regulatory agencies (eg, US Food and Drug Administration), and are the product of a negotiation between the drug's sponsor and the regulators. Labels are intended to provide important information for prescribers, pharmacists, and patients regarding the drug's indication(s) and toxicities, but also include information regarding the drug's pharmacokinetics, which may not be of interest to most prescribers. However, the label for lapatinib1 (approved by the US Food and Drug Administration on March 13, 2007) includes a number of pharmacokinetic details of high interest to both prescribers and patients. A most notable finding—also presented at the 2007 meeting of the American Society for Clinical Pharmacology and Therapeutics2—is that the bioavailability of lapatinib is greatly increased by food, especially a high-fat meal. A randomized, cross-over, food-effect study demonstrated that both peak concentration and area under the concentration–time curve were increased markedly when a single 1,500-mg dose of lapatinib was taken with food as opposed to when fasting, and was increased further by a high-fat meal. The (geometric) mean increase for the area under the concentration–time curve was 167% for low-fat meals and 325% for high-fat meals. These results are not surprising, given that food often increases a drug's bioavailability.3,4 So why does the lapatinib package insert, including the patient information, indicate, "TYKERB should be taken at least one hour before, or at least one hour after, food"? The answer is fairly straightforward: this is how the sponsor conducted its pivotal phase III trial5—the sponsor apparently did not know the result of the food effect study. Thus, the officially recommended dose must match the dose used in the pivotal trial, which was five 250-mg tablets taken fasting. The recommendation for 1,250 mg fasting is even more problematic in light of the required colabeling with capecitabine, which is administered bid (approximately 12 hours apart) with food and has its own independent dosing issues.6 Obviously, it would be much easier for patients to take all of their pills at one time with food, as opposed to having to deal with the complexity of taking one set of pills fasting and one set of pills with food. The economic implications of this food effect study are particularly remarkable. At the current price of $2,900 per month,7 a cost savings of 60% or $1,740 per month would be realized if the drug were taken with food. If one were so inclined, there are also opportunities for additional cost savings through dietary modification. The package insert notes that strong CYP3A inhibitors, including grapefruit juice, "may also increase plasma concentrations." Thus, it is possible that one 250-mg lapatinib pill, accompanied by food and washed down with a glass of grapefruit juice, may yield plasma concentrations comparable to five 250-mg pills on an empty stomach, which would result in a total cost savings of 80% (minus the cost of the food and juice). As a separate issue, the lapatinib label also notes that dividing the daily dose results in a doubling of drug exposure, which would be another approach that may allow a reduction in the number of daily pills (and costs). There would also be potential clinical benefit to using a lower dose of lapatinib with food. Diarrhea is a major toxicity of lapatinib, and it is suggested that this effect is due to unabsorbed drug, given that its frequency is better correlated with dose than with plasma concentration.8 Thus, 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. The use of a lower dose with food would also mitigate the potential risk of standard doses of lapatinib with food, which could increase the risk of toxicity. In recent years, there has been an increased enthusiasm for development of oral agents, which is based on both clinical and economic motivations.9,10 This includes both completely new agents and analogs of existing parenteral agents, such as capecitabine. The development of oral agents requires a much greater knowledge of a drug's clinical pharmacology than with parenteral development, because of the multitude of factors that can affect bioavailability (eg, food, dose, and concomitant oral medications).9 Furthermore, the rapidly escalating price of medications (especially for cancer and other life-threatening diseases) has provided incentives to explore pharmacologic approaches to lower the costs of drugs. Thus, ketoconazole has been combined with cyclosporine, tacrolimus, and sirolimus to decrease the cost of transplant rejection prophylaxis.11-13 Grapefruit juice also has the potential to be used to lower drug costs by increasing oral bioavailability, due to the effects of furanocoumarins.14-16 In fact, we currently are conducting a prospective phase I trial of the combination of oral sirolimus (rapamycin) and grapefruit juice,17 with the intention of developing the least expensive approach possible to inhibit the mammalian target of rapamycin.18 Therefore, as we enter an era of targeted anticancer agents with a monthly cost measured in thousands of dollars, we should view drug-drug or drug-food interactions as opportunities to lower costs. This is particularly true for marketed drugs that have already been priced, such as lapatinib. So where do we go from here? The one thing that should not be anticipated is an efficacy study conducted by the sponsor of lapatinib (GlaxoSmithKline, Philadelphia, PA) comparing two 250-mg tablets with food to five 250-mg tablets fasting. However, such a study could be mounted by a number of other entities, including the federal government, other payors, or advocacy groups. Alternatively, physicians could simply extrapolate from the existing pharmacokinetic and clinical data and prescribe 500 mg (two 250-mg tablets) daily with food, at 40% of the current cost for the drug. It is important, however, to emphasize that we strongly recommend study of a lower dose with food, rather than routine prescribing without a formal pharmacokinetic study. Given that lapatinib may have nonlinear pharmacokinetics (as illustrated by the equivocal relationship between dose and exposure,8 and higher exposure with divided doses), the magnitude of the effect of food at a lower dose may differ from that observed at 1,500 mg. It is also possible that the degree of interpatient variability (coefficient of variation in oral clearance of 48%)19 may be affected by food, although this was not demonstrated in the food effect study.2 Finally, the effects of food on chronic dosing are unknown, although the single published phase I study of chronic dosing did not control for food after the first dose.8 One remedy for the sponsor would be development of a new and improved (and significantly more expensive) 500-mg formulation, which would be dosed with food rather than fasting. This would be slightly easier for patients than taking two 250-mg tablets with food, but more importantly could allow the sponsor to salvage the market that would be lost through widespread adaptation of the so-called value meal–based dosing of lapatinib. Of course, this financial remedy would also require the sponsor to eliminate the competition by withdrawing their current 250-mg formulation, so stock up while you can. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: None Consultant or Advisory Role: Mark J. Ratain, Onyx (C), Abbott (C), Genzyme (C), Takeda (C), Bristol-Myers Squibb (C); Ezra E. Cohen, GlaxoSmithKline (C), Genentech (C), AstraZeneca (C), Boehringer Ingelheim (C), OSI (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Renumeration: None AUTHOR CONTRIBUTIONS Conception and design: Mark J. Ratain, Ezra E. Cohen Manuscript writing: Mark J. Ratain, Ezra E. Cohen Final approval of manuscript: Mark J. Ratain, Ezra E. Cohen NOTES published online ahead of print at www.jco.org on July 16, 2007. REFERENCES 1. GlaxoSmithKline: TYKERB label. http://us.gsk.com/products/assets/us_tykerb.pdf 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. Singh BN, Malhotra BK: Effects of food on the clinical pharmacokinetics of anticancer agents: Underlying mechanisms and implications for oral chemotherapy. Clin Pharmacokinet 43:1127-1156, 2004[CrossRef][Medline] 4. Li Z, Vachharajani NN, Krishna R: On the assessment of effects of food on the pharmacokinetics of drugs in early development. Biopharm Drug Dispos 23:165-171, 2002[CrossRef][Medline] 5. Geyer CE, Forster J, Lindquist D, et al: Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733-2743, 2006 6. Ratain MJ: Dear doctor: We really are not sure what dose of capecitabine you should prescribe for your patient. J Clin Oncol 20:1434-1435, 2002 7. Graedon J, Graedon T: http://www.peoplespharmacy.com/archives/editorial/cancer_drug_prices_continue_to_soar.asp 8. Burris HA III, Hurwitz HI, Dees EC, et al: Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305-5313, 2005 9. DeMario MD, Ratain MJ: Oral chemotherapy: Rationale and future directions. J Clin Oncol 16:2557-2567, 1998[Abstract] 10. Parsad SD, Ratain MJ: Prescribing oral chemotherapy. BMJ 334:376, 2007 11. el-Agroudy AE, Sobh MA, Hamdy AF, et al: A prospective, randomized study of coadministration of ketoconazole and cyclosporine a in kidney transplant recipients: Ten-year follow-up. Transplantation 77:1371-1376, 2004[CrossRef][Medline] 12. Soltero L, Carbajal H, Rodriguez-Montalvo C, et al: Coadministration of tacrolimus and ketoconazole in renal transplant recipients: Cost analysis and review of metabolic effects. Transplant Proc 35:1319-1321, 2003[CrossRef][Medline] 13. Thomas PP, Manivannan J, John GT, et al: Sirolimus and ketoconazole co-prescription in renal transplant recipients. Transplantation 77:474-475, 2004[CrossRef][Medline] 14. Bressler R: Grapefruit juice and drug interactions: Exploring mechanisms of this interaction and potential toxicity for certain drugs. Geriatrics 61:12-18, 2006[Medline] 15. Kakar SM, Paine MF, Stewart PW, et al: 6'7'-Dihydroxybergamottin contributes to the grapefruit juice effect. Clin Pharmacol Ther 75:569-579, 2004[CrossRef][Medline] 16. Paine MF, Widmer WW, Hart HL, et al: A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr 83:1097-1105, 2006 17. National Institutes of Health: Ph Ib Rapamycin with grapefruit juice for advanced malignancies. http://clinicaltrials.gov/show/NCT00375245 18. Cho D, Signoretti S, Regan M, et al: The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res 13:758s-763s, 2007 19. Center for Drug Evaluation and Research: Application 22-059. http://www.fda.gov/cder/foi/nda/2007/022059s000_ClinPharmR.pdf
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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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