Torizel

Uses

Torizel is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR.

For the treatment of renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma.

Torizel is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma

How Torizel works

Torizel is an inhibitor of mTOR (mammalian target of rapamycin). Torizel binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor.

Toxicity

Torizel has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of temsirolimus, which may increase its serum concentration.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of temsirolimus and may reduce its serum concentration.

[Moderate] GENERALLY AVOID: Coadministration of temsirolimus with grapefruit juice may increase the plasma concentrations of sirolimus, a major active metabolite of temsirolimus and known substrate of CYP450 3A4.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruits.

MANAGEMENT: Patients treated with temsirolimus should preferably avoid the consumption of grapefruit or grapefruit juice.

Torizel Cholesterol interaction

[Moderate] Elevations in cholesterol and triglyceride levels have been reported in patients taking inhibitors of mTOR (mammalian target of rapamycin).

Monitoring of fasting lipid profile is recommended prior to the start of therapy and periodically thereafter.

Clinicians should achieve control of lipid levels before initiating therapy with these agents.

Torizel Drug Interaction

Major: enoxaparinModerate: paclitaxel protein-bound, zolpidem, fluconazole, amlodipine, alprazolamUnknown: amphetamine / dextroamphetamine, lorazepam, sulfamethoxazole / trimethoprim, ethanol, levetiracetam, polyethylene glycol 3350, oxycodone, omeprazole, omeprazole, pantoprazole, tramadol, acetaminophen / hydrocodone, cholecalciferol, ranitidine

Torizel Disease Interaction

Major: vaccination, renal disease, GI perforation, hypersensitivity, liver diseaseModerate: blood glucose, cholesterol, Infections, wound complication, lung dysfunction

Volume of Distribution

172 L in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements

Elimination Route

Infused intravenous over 30 - 60 minutes. C_max is typically observed at the end of infusion

Half Life

Torizel exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, respectively.

Clearance

16.2 L/h (22%)

Elimination Route

Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection.

Innovators Monograph

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