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In Reply

Department of Medicine, University of Chicago, Chicago, IL

We are pleased to respond to the letters of Koch and colleagues, Rahman and colleagues, Messori, and Trippoli regarding our Comments and Controversies article in the August 10, 2007, issue of the Journal of Clinical Oncology. We continue to believe that concerns related to current drug development, specifically surrounding safety and pricing, are exemplified by the approval of lapatinib in the United States.

In the letter from Koch et al, the authors, who are all employees of GlaxoSmithKline, emphasize the importance of clinical pharmacology studies in drug development. They indicate that they intentionally conducted their pivotal study using 1,250 mg fasting because of concerns regarding interindividual pharmacokinetic variability with food. This is apparently because of data from one or more unpublished food effect studies using a dose of 100 mg, demonstrating a moderate food effect (60% increase with a high-fat meal). Notably, these other studies with lower dosages do not appear to have been a consideration in regard to labeling, as they were not cited in the US Food and Drug Administration (FDA) Clinical Pharmacology and Biopharmaceutics Review document.¹ Thus, it is still unclear to us how the company could have made the decision to develop lapatinib in a manner that results in the lowest possible bioavailability, especially given the concerns of Koch and colleagues regarding the narrow therapeutic index of lapatinib.

Let us elaborate further on why we think that the company made the wrong decision for the design of their pivotal trial. Although they may have had information regarding the moderate effect of a high-fat meal with a 100-mg dose of lapatinib, they had no information regarding the marked food effect demonstrated at higher doses. Furthermore, they had no information regarding the therapeutic index of lapatinib, as no dose-ranging phase II studies were performed. Thus, it is only speculative that a decreased exposure would diminish efficacy. In contrast, the US FDA Clinical Pharmacology and Biopharmaceutics Review includes a detailed analysis of lapatinib-induced QT prolongation, and the Executive Summary states that administration of lapatinib with food "would be expected to further prolong the QTc interval," a risk factor for torsades de pointe and/or sudden death.²

Rahman et al (all employees of the US FDA) further emphasize that the coadministration of an agent with a narrow therapeutic index whose exposure is apparently markedly increased with food carries potentially serious risk. However, we are surprised by the conclusion of the US FDA authors that the single-dose food effect study in 27 patients (at a dose of 1,500 mg) provides any insight regarding the relative tolerability of the labeled 1,250-mg dose without food versus a lower 500-mg dose with food. In addition to gastrointestinal toxicity due to unabsorbed drug, we are concerned about tolerability of chronic dosing, particularly cardiac toxicity in the context of the comments in the formal US FDA review regarding QT prolongation.¹

The other two letters by Messori and Trippoli, respectively, further cite the risk of taking lapatinib with food, including potential medicolegal implications. We share the concern expressed in these letters and do not recommend off-label administration of lapatinib outside of a clinical trial. Messori's theoretical concerns regarding the effect of food on interpatient variability are valid, but are not supported by the studies to date and should be addressed in future pharmacokinetic studies. We agree with Trippoli that taking lapatinib with food has medicolegal implications, particularly if coadministration with food occurs unintentionally at the standard dose, as complex instructions involving food-dosing restrictions are frequently misunderstood by patients.³ We also agree with Trippoli that drug prices should be based on value, but such pricing approaches, which are widely utilized around the world, are not utilized by the public sector in the United States.⁴

Prescribers and patients generally expect that a drug will be labeled to maximize bioavailability, and would most likely anticipate that the consequences of refusal to fast would be a decrease in efficacy, not an increased risk of toxicity. Aside from the unnecessary cost and the potential for increased GI toxicity due to unabsorbed drug, we think this constitutes a significant cardiac risk to patients with breast cancer receiving lapatinib.

Thus, given the dramatic increase in bioavailability of lapatinib with a high-fat meal, its effect on QT interval, and the potential for nonadherence with dosing instructions, we have serious concerns regarding the safety of this particular combination in a diverse patient population, as based on the current product label. Thus, we would urge GlaxoSmithKline and the US FDA to modify the lapatinib label to include a strong and clear warning regarding the risk of cardiac toxicity if the drug is taken with food, particularly a high-fat meal. In fact, the US FDA's Clinical Pharmacology and Biopharmaceutics Review suggested that the label should include "the potential for an increased risk of QTc prolongation as a result of factors that could increase lapatinib concentrations such as coadministration of CYP3A4 inhibitors, administration of drug with food, or administration to patients with hepatic impairment." Notably, there is no mention in either the QT Prolongation section of the Warnings and Precautions or the Patient Information regarding the potential irreversible effects of taking lapatinib with food.

We also believe that GlaxoSmithKline has the obligation to study a lower dose of lapatinib with food (with or without encouragement from the US FDA), despite the potential negative impact on sales. It would be a poor business decision to target maximum sales at the potential cost of exposing a large number of patients with breast cancer to the risks of having fried eggs with 1,250 mg of lapatinib.

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: None Consultant or Advisory Role: Mark J. Ratain, Onyx (C), Abbott (C), Genzyme (C), Takeda (C), Bristol-Myers Squibb (C), OSI (C); Ezra E.W. Cohen, GlaxoSmithKline (C), Genentech (C), AstraZeneca (C), Boehringer Ingelheim (C), OSI (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCES

1. Center for Drug Evaluation and Research: Application 22-059. http://www.fda.gov/cder/foi/nda/2007/022059s000_ClinPharmR.pdf

2. Kannankeril PJ, Roden DM: Drug-induced long QT and torsade de pointes: Recent advances. Curr Opin Cardiol 22:39-43, 2007[Medline]

3. Stone VE, Hogan JW, Schuman P, et al: Antiretroviral regimen complexity, self-reported adherence, and HIV patients' understanding of their regimens: Survey of women in the her study. J Acquir Immune Defic Syndr 28:124-131, 2001[CrossRef][Medline]

4. Barton JH, Emanuel EJ: The patents-based pharmaceutical development process: Rationale, problems, and potential reforms. JAMA 294:2075-2082, 2005[Abstract/Free Full Text]

Related Correspondence

• The Value of Label Recommendations: How to Dose Lapatinib
  Kevin M. Koch, Andrew P. Beelen, Peter T.C. Ho, and Debasish F. Roychowdhury
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• Effect of Food on Lapatinib Pharmacokinetics
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  JCO 2007 25: 5332-5333 [Full Text]
• Controversies in Using Lapatinib at Reduced Dosage With Food
  Sabrina Trippoli
  JCO 2007 25: 5333 [Full Text]
• The Value Meal: Effect of Food on Lapatinib Bioavailability
  Atiqur Rahman, Richard Pazdur, Yaning Wang, Shiew-Mei Huang, and Lawrence Lesko
  JCO 2007 25: 5333-5334 [Full Text]

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