Flushing Oral Oncology Drugs Down the Toilet

Although the systemic treatment of cancer has historically relied on intravenous administration of cytotoxic drugs, oncologists have focused more recently on oral drugs developed to inhibit specific targets. The treatment of many cancers is now more akin to the treatment of serious chronic diseases, such as HIV. These newer targeted oral drugs generally also have a wider therapeutic index than conventional cytotoxic drugs. The prescriber of oral drugs must consider a number of issues that are not relevant to parenteral drugs. This includes considerations of specific drug strengths, number of pills, interacting oral medications, food effects on bioavailability, and adherence. These issues are interrelated; adherence is often inversely correlated with the complexity of a drug regimen. The effect of food is a particular concern in the labeling of drugs, generally with the intent to maximize absorption and drug exposure. Many drugs are labeled to be taken either with or without food, because the effects of food are not clinically significant. However, those drugs whose absorption is decreased by taking with food are generally labeled to be taken fasting (ie, no food for 2 hours before or 1 hour after dosing), whereas those drugs whose absorption is increased by food are generally labeled to take with meals. However, a recent study of oral agents approved by the US Food and Drug Administration in the last 10 years demonstrated that oral oncology drugs have generally been labeled fasting, despite food effects as large as a four-fold increase in bioavailability. The apparent bias for fasting labeling of oncology drugs is exemplified by abiraterone acetate, which was approved for marketing in the United States on April 28, 2011, for the treatment of metastatic prostate cancer. Abiraterone acetate is a prodrug of abiraterone, an inhibitor of CYP17 that decreases extratesticular formation of androgens. Most notably, it has a food effect greater than any other marketed drug (fiveto 10-fold, depending on fat content), yet it is labeled to be taken fasting. The marked effect of a high-fat meal (10-fold increase in exposure) implies that absolute bioavailability in the fasting state is no more than 10%. This is likely the result of low absorption under fasting conditions, because 77% of the administered drug is excreted as abiraterone (or its prodrug acetate) in feces. In addition, there is marked interindividual pharmacokinetic variability, with a coefficient of variation in the plasma concentration area under the curve of 59% under labeled conditions. In a recent editorial, the authors (from the US Food and Drug Administration) expressed concern about the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications, suggesting a preference for labeling drugs under fasting conditions, even if bioavailability were markedly increased by food. There is no evidence that this concern is valid for all oral anticancer drugs, and even less evidence that it is true for ambulatory men with metastatic prostate cancer, who may have a preference for taking their medications with a bowl of cereal to make an early morning tee time. There is also no evidence that intraindividual variability in diet is greater for patients with cancer than those taking daily oral medications for other chronic life-threatening conditions such as HIV, hepatitis C, or solid organ transplantation. If the US Food and Drug Administration were truly concerned about intraindividual variability in diet, why has this never come up in the labeling of nononcology drugs? Should the US Food and Drug Administration be more concerned about an effective overdose or underdose, given the risk of poor adherence to food-effect labeling? This author would argue that the risk of overdose is clearly more compelling, as illustrated by the label for nilotinib, another drug with a clinically significant food effect that is labeled to be taken fasting. Nilotinib is unique; its label incorporates a black-box warning regarding the potential for food to increase the drug risk of QT prolongation and sudden death. In an attempt to mitigate this risk, the US Food and Drug Administration initiated a risk evaluation and mitigation strategy last year, including the required use of a drug timing dial for patients and their prescribers. Did the US Food and Drug Administration have any options in its review of the abiraterone acetate new drug application, given that the phase III study demonstrated a survival advantage for patients with castration-resistant prostate cancer treated with this hormonal agent? Certainly the US Food and Drug Administration was aware of the food-effect data from early studies and could have required the sponsor to conduct at least one randomized study using fed dosing (eg, standard breakfast) so that the drug could have been labeled to be taken with food. The US Food and Drug Administration also had the authority to require such studies as a postmarketing requirement, but it chose not to do so. The lack of attention of the US Food and Drug Administration to this issue is even more problematic given the implicit concern in their approval letter regarding increased exposure as a result of concomitant usage of strong CYP3A4 inhibitors. This concern is well founded but of much less concern than the more obvious problem of a fiveto 10-fold increase in drug concentrations resulting from simple patient error, such as eating breakfast 30 minutes after taking abiraterone acetate. This seems to be more than an issue with a single drug label and may be a manifestation of a systematic process within the US Food and Drug Administration that has not been publicly debated. The recent labeling of oral oncology drugs is inconsistent with labeling in other JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 29 NUMBER 30 OCTOBER 2