Grapefruit juice increases bioavailability of rapamycin

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Grapefruit juice increases bioavailability of rapamycin

Cohen EEW, Hartford C, Maitland ML, et al. Grapefruit juice significantly increases bioavailability of weekly rapamycin (sirolimus) - evidence of safety and activity in a phase 1 study. Abstract #LB-135. 100th Annual Meeting of the American Association for Cancer Research. Poster Section 27. Denver April 20, 2009.



Background: mTOR inhibitors have activity in several cancers. The class prototype, rapamycin (R), has low oral bioavailability. Grapefruit juice (GJ) contains furanocoumarins that increase bioavailability of many drugs that undergo P450 metabolism. We hypothesized that GJ would increase AUC of R administered weekly, allowing tolerable, convenient, and cost-effective delivery of an mTOR inhibitor.
Methods: R was administered orally once weekly using an adaptive escalation design based on AUC. R alone was administered in week 1 and with GJ (240 ml QD) from week 2 onwards. Pharmacokinetic parameters were compared with and without GJ. Patients with non-measurable disease were permitted to enroll.
Results: 28 subjects [15 males and 13 females (ages 27 - 77)] with advanced solid tumors were enrolled. R was escalated in cohorts of 15 (n=5), 20 (n=5), 25 (n=5), and 35 (n=13) mg. The table shows mean AUC and Cmax of R vs. R+GJ. Dose limiting toxicity was observed in 2 subjects at 25 mg (grade 3 hyperglycemia) and 35 mg (grade 3 mucositis). The most commonly observed toxicities were hyperglycemia (75%), diarrhea (68%), lymphopenia (57%), fatigue (54%), and hyperlipidemia (50%). Of the 25 evaluable subjects, best observed responses included 1 partial response and 7 stable disease. The partial response was observed in a patient diagnosed with metastatic epithelioid hemangioendothelioma who had been previously treated with sorafenib and has received R+GJ for 40 weeks.
Conclusions: The addition of GJ to R significantly increases the AUC and Cmax of R approximately 4-fold and 2-fold, respectively. The combination of R+GJ is well tolerated without unexpected toxicities. R exposure at 35 mg po is at least comparable to that achieved with temsirolimus 25 mg iv. Further studies are indicated in tumors of vascular origin as well as other malignancies (e.g., renal cancer).