Ketoconazole, Grapefruit Juice Increase Pharmacokinetics of Sirolimus

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(ChemotherapyAdvisor) – Ketoconazole or grapefruit juice increase the pharmacokinetics of sirolimus, according to a team of US-based researchers. This conclusion is based on a study entitled “Phase I Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients,” which is published in the August issue of Clinical Cancer Research

In this study, the investigators aimed to determine the tolerability of sirolimus analogs in combination with pharmacokinetic modulators. To meet this aim, the investigators conducted 3 Phase 1 studies of sirolimus, simultaneously, in advanced cancer patients. In this adaptive escalation design, patients (N = 138) received, on a weekly basis, a dose of oral sirolimus alone or in combination with either ketoconazole or grapefruit juice.

The investigators provided some interesting findings. The maximum effect of treatment was achieved at 90, 16, and 25mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively, with ketoconazole and grapefruit juice increasing the pharmacokinetics of sirolimus by approximately 500% and 350%, respectively. The investigators reported that 1 partial response, which was observed in a patient with epithelioid hemangioendothelioma. In terms of tolerability, sirolimus was generally well tolerated – the most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively.  

The investigators concluded that “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.”


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