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Grapefruit juice, ketoconazole increased sirolimus levels in patients with advanced cancer
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One glass of grapefruit juice each day significantly slowed the body’s metabolism of sirolimus, suggesting patients still could derive benefits by taking lower doses of the anticancer drug, according to study results.
Patients with advanced cancer who consumed 8 oz of grapefruit juice daily more than tripled their levels of sirolimus (Rapamune, Wyeth Pharmaceuticals), an mTOR inhibitor that has been approved for use in transplant patients and also has been shown to help those with cancer.
The drug ketoconazole, commonly used to treat infections, raised patients’ sirolimus levels by 500%, according to researchers.
Grapefruit juice inhibits the enzymes that break down several drugs, including sirolimus, according to background information provided by the researchers.
“Grapefruit juice, and drugs with a similar mechanism, can significantly increase blood levels of many drugs, but this has long been considered an overdose hazard,” Ezra Cohen, MD, an associate professor at the University of Chicago Medicine who has conducted extensive research into the role molecularly targeted agents can play in treatment of head and neck, thyroid and salivary gland cancers, said in a press release.
Cohen and colleagues conducted the study to determine whether controlled use of grapefruit juice could increase the levels and effectiveness of sirolimus.
Cohen and colleagues enrolled 138 patients with incurable cancer and no known effective treatment.
The patients were divided into three groups: sirolimus only, sirolimus plus ketoconazole or sirolimus plus grapefruit juice.
The researchers began by administering low sirolimus doses to patients in each group, then gradually increased the doses to reach a target level — area under the concentration curve (AUC) 3,810 ng-h/mL, equal to that achieved with a 25-mg dose of temsirolimus IV — at which patients received the greatest disease-fighting effect with the least toxicity.
In the sirolimus-only patients, the target AUC was achieved at a dose of about 90 mg per week. However, doses of at least 45 mg triggered serious gastrointestinal adverse effects, such as nausea and diarrhea, so doses for patients assigned to sirolimus only eventually were reduced to 45 mg per week.
The doses required to reach the target AUC were lower for patients in the sirolimus plus ketoconazole arm (16 mg) and the sirolimus plus grapefruit juice arm (25 mg to 35 mg), according to study results.
No patients in any of the groups demonstrated complete response. One demonstrated partial response, described as significant tumor shrinkage that lasted for more than 3 years. Overall, about 30% of patients had stable disease.
The most commonly observed adverse events reported overall were hyperglycemia (52%), hyperlipidemia (43%) and lymphopenia (41%).
Although ketoconazole demonstrated better drug retention, grapefruit juice offers other advantages.
“We have at our disposal an agent that can markedly increase bioavailability and, critically in the current environment, decrease prescription drug spending on many agents metabolized by P450 enzymes,” Cohen and colleagues wrote.
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