Grapefruit Juice Increases Bioavailability of mTOR Inhibitor; Turning a Problem with Oral Therapies into an Advantage

ImageGrapefruit juice is known to interfere with the metabolism of numerous drugs, and patients on those drugs are often warned to avoid the fruit. Now, researchers at the University of Chicago have found a way to turn that disadvantage into an advantage for sirolimus, a commercially available mTOR inhibitor. If optimized, the approach could reduce drug costs for a wide variety of oral cancer agents, according to the study authors. “What has been perceived as a problem of drug-food interactions, we really saw as an opportunity to enhance the bioavailability of this drug, sirolimus, because we know that very little of it actually does get absorbed,” said lead author Ezra Cohen, MD, Associate Professor of Medicine at the University of Chicago Comprehensive Cancer Center. To test the juice's ability to increase drug bioavailability, Cohen and colleagues enrolled 138 patients with advanced cancer in one of three phase I trials. Patients in the trials received sirolimus, sirolimus plus ketoconazole, or sirolimus plus grapefruit juice.EZRA E.W. COHEN, MD: “The pathway that grapefruit juice inhibits is the main set of metabolizing enzymes for oral drugs—the CYP3A-cytochrome p450 pathway. Almost every oral oncology drug now on the market is metabolized through this pathway, and many, many more are in development.”Ketoconazole reduced the amount of drug required to reach the desired area under the concentration curve (AUC; 3,810 ng-h/ml) by 500 percent, whereas grapefruit juice reduced it by 350 percent. In absolute terms, the once weekly dose required to reach the target AUC was 16 mg for patients taking sirolimus plus ketoconazole, 25 mg for patients taking sirolimus plus grapefruit juice, and 90 mg for patients taking sirolimus alone. Despite the absolute differences in dosing, the researchers saw no significant differences in adverse events between the three drug regimens. Cohen acknowledges that there are challenges for developing grapefruit juice as a modifier of drug uptake. For example, the team's initial studies used an off-the-shelf type of grapefruit juice, which had minimal inhibitory effect on the metabolic enzymes. By contrast, freshly frozen juice was a potent inhibitor of the CYP3A enzyme and effectively increased the bioavailability of sirolimus. Therefore, grapefruit juice would need to be standardized and clear directions regarding storage and use provided to patients—similar to what is done for drugs themselves. Funding Another major hurdle is funding. The group has approached several government organizations, including Health Canada and the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP), as well as a third-party payer, but have not yet found a group willing to support further development of the strategy. “There is no doubt that the development of these ideas is going to cost something,” Cohen told OT. “But if we look at it in the context of how much these drugs cost now, you see the cost savings quickly begin to be realized once the clinical trials are done. Many oral oncology drugs run at $5k per month, sometimes more. We have the potential to reduce the amount of drug needed by half—or in some cases, like sirolimus, by 60 to 70 percent.” Expanding Opportunity Although the current work, now available online ahead of print in Clinical Cancer Research (doi: 10.1158/1078–0432.CCR-12–0110), tests grapefruit juice's ability to affect the bioavailability of a single drug, Cohen and others emphasize that the principle also applies to other oral agents. “The pathway that grapefruit juice inhibits is the main set of metabolizing enzymes for oral drugs,” he said. “It is the CYP3A-cytochrome p450 pathway. Almost every oral oncology drug now on the market is metabolized through this pathway, and many, many more are in development.” Cohen also notes that the issue of drug-diet interaction is going to become a more pressing issue for oncologists, as more oral drugs come into the clinic: “In that sense, we've been spoiled in oncology because most of the agents we have administered are IV, so as medical oncologists we haven't had to worry about these things.” “Clearly now it is a much bigger issue,” he continued, pointing to an editorial he wrote with senior author Mark Ratain, MD, a few years ago about the impact of taking lapatinib with or without food (JCO 2007;25:3397–3398). “Some drugs need to be taken with food, some on an empty stomach, some can be taken with food, but you need to avoid fatty foods. So it is really something that as physicians we need to be educated in—and patients really need to adhere to the labels.” ‘Very Careful Implementation Needed’ Asked for his opinion, Jan Schellens, MD, PhD, Professor of Clinical Pharmacology at The Netherlands Cancer Institute in Amsterdam, who studies drug bioavailability, said he is enthusiastic but cautious about the approach. “Drs. Cohen and Ratain repeatedly make valid points,” he wrote in an email message. “Personally I am very much in favor of strategies to improve oral bioavailability. I believe variability will be reduced, therapy outcomes may improve, and costs may be reduced. “Whether one can standardize grapefruit juice intake or food to improve bioavailability in general practice needs additional studies and very careful implementation,” he continued. “It seems a simple ‘trick,’ but as with everything it may work well in the research environment but then turn out to be more complex in general practice.” Presented at ASCO and AACR Meetings Parts of the study were presented in abstract form at the 2006, 2007, and 2008 ASCO Annual Meetings as well as the 2009 AACR Annual Meeting.

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