As the treatment of cancer shifts increasingly toward more oral therapies, patients are now partly responsible for when and how they take their medication. Despite the potential for increased absorption if medications are taken with food, most oncology drug labels warn patients to take the drug while fasting.
Last fall, Dr. Mark J. Ratain brought up the issue of increased utilization of oral cancer treatment in the context of patient adherence and optimal utilization in an article in the Journal of Clinical Oncology entitled “Flushing Oral Oncology Drugs Down the Toilet.”[1]
Dr. Ratain, professor of medicine and the director of the Center for Personalized Therapeutics at the Comprehensive Cancer Center at the University of Chicago School of Medicine, takes particular issue with the way that most oncology drug labels recommend taking the pills while fasting. The effect of food “is a particular concern in the labeling of drugs, generally with the intent to maximize absorption and drug exposure,” he says. However, he says that these labels are sometimes used despite evidence that food increases bioavailability of the medication as much as four-fold, citing a recent study that he coauthored, “Inconsistent Labeling of Food Effect for Oral Agents Across Therapeutic Areas: Differences Between Oncology And Non-Oncology Products.”[2]
The broader issue here is the potential inefficiency of the process by which pharmaceutical and biotechnology companies develop drugs, and a lack of acknowledgement of this by the US Food and Drug Administration (FDA). The FDA has highlighted the effect of food on drug absorption and the high variability of this effect between individuals. Because of this variability, the FDA prefers to have a fasting label on oncology medications as a default.
Dr. Ratain uses as an example abiraterone acetate (Zytiga), a prodrug of abiraterone that was recently approved for the treatment of prostate cancer. Abiraterone acetate decreases the extra-testicular production of androgens. The drug has a 5- to 10-fold better absorption when taken with food, depending on the fat content of the latter. But, abiraterone acetate’s label says to take the drug while fasting, meaning that only 10% of the drug is actually absorbed if the patient adheres to the label instructions. Dr. Ratain argues that the FDA, since it has the bioavailability data at hand, should have required a post-marketing study to assess the efficacy of abiraterone acetate in patients taking the pill with their standard breakfast. Such a study might save patients and payers money in the long term.
Part of the problem is determining whether it is better to potentially overdose or underdose, but this is likely to be an individual drug issue. The central concern, according to Dr. Ratain, is that “labeling of oral oncology drugs is inconsistent with labeling in other therapeutic areas as well as with fundamental principles of clinical pharmacology.”
A reply to Dr. Ratain’s article, published earlier this month in the Journal of Clinical Oncology by authors from the research and development division at Janssen, the subsidiary of Johnson & Johnson that manufactures abiraterone acetate, stresses that the risks of toxicity at higher absorption levels for oncology drugs are higher than for other types of medications. The authors write: “For drugs with higher risks of toxicity, even moderate changes in pharmacokinetics might substantially increase toxicity without necessarily increasing efficacy. Such is the case with many oral oncology drugs.”[3]
The Janssen response argues that while fasting is a baseline that all patients can be made to adhere to, taking an oral oncology medication with food is not reproducible due to variations in calories, fat content, and multiple absorption and genetic factors of individuals. They highlight that the dosing was chosen and approved based on careful consideration of these factors and on the results of large-scale patient trials and consideration of early phase I data showing different drug exposures with co-consumption of food.
The Janssen research and development team believe that because physicians cannot control the food or the schedule of food consumption of patients, fasting is the most practical approach.
In his reply to the commentary, Dr. Ratain points out that, indeed, it is difficult to control the daily meal schedule of cancer patients but that the drug companies, and specifically Janssen, do not help their cause through the promotion of proper fasting and on-label use, or by stressing the need to take the medication on an empty stomach. Dr. Ratain asserts that the source of the bias, whether from the FDA or from the drug companies, should be resolved.
Reference
1. Ratain MJ. Flushing oral oncology drugs down the toilet. J Clin Oncol. 2011;29:3958-3959.
2. Kang SP, Ratain MJ. Inconsistent labeling of food effect for oral agents across therapeutic areas: differences between oncology and non-oncology products. Clin Cancer Res. 2010;16:4446-4451.
3. Todd M, Meyers ML, Charnas R, et al. Fast and Flawed or Scientifically Sound: The Argument for Administering Oral Oncology Drugs During Fasting. J Clin Oncol. 2012 Feb 13. [Epub ahead of print]
