Grapefruit juice interacts with various drugs by slowing drug metabolism, thus increasing their concentrations in the body. Based on this fact, numerous drugs are labeled to restrict use of grapefruit juice during therapy.
However, researchers associated with The University of Chicago Medicine, interested in how to "harness this drug-food interaction," have now found in a study of one drug that "patients who drank 8 ounces a day of grapefruit juice increased their sirolimus levels by 350 percent." A press release from the university states that this intentional drug-food combination "could help patients avoid side effects associated with high doses of the drug and reduce the cost of the medication," and the authors state that dose-finding studies are "not necessarily profitable" for drug makers.
Clinical Cancer Research
August 7, 2012; doi: 10.1158/1078-0432.CCR-12-0110
Phase I Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients
Purpose: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.
Experimental Design: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.
Results: Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.
Conclusion: Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs.