indication

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

mechanism of action

Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus 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

Temsirolimus 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.

biotransformation

Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation.

absorption

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

half life

Temsirolimus 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.

route of elimination

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.

drug interactions

Aminoglutethimide: Aminoglutethimide may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Amprenavir: Amprenavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Atazanavir: Atazanavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Bosentan: Bosentan may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Carbamazepine: Carbamazepine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Clarithromycin: Clarithromycin may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Conivaptan: Conivaptan may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Darunavir: Darunavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Delavirdine: Delavirdine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Dexamethasone: Dexamethasone may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Efavirenz: Efavirenz may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Fluorouracil: Co-administration of Temsirolimus and Fluorouracil may result in serious adverse drug reactions.

Fosamprenavir: Fosamprenavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Fosphenytoin: Fosphenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Gemcitabine: Co-administration of Temsirolimus and Gemcitabine may result in serious adverse drug reactions.

Imatinib: Imatinib may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Indinavir: Indinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Isoniazid: Isoniazid may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Itraconazole: Itraconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Ketoconazole: Ketoconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Lopinavir: Lopinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Miconazole: Miconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Nafcillin: Nafcillin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Natalizumab: Temsirolimus may increase the toxicity of Natalizumab. Concomitant therapy should be avoided.

Nefazodone: Nefazodone may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Nelfinavir: Nelfinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Nevirapine: Nevirapine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Nicardipine: Nicardipine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Oxcarbazepine: Oxcarbamazepine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Pentobarbital: Pentobarbital may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Phenobarbital: Phenobarbital may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Phenytoin: Phenytoin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Posaconazole: Posaconazole may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Primidone: Primidone may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Quinidine: Quinidine may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Rifabutin: Rifabutin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Rifampin: Rifampin may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Rifapentine: Rifapentine may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Ritonavir: Ritonavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Saquinavir: Saquinavir may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

St. John's Wort: St. John's Wort may increase the metabolism of Temsirolimus decreasing its efficacy. Concomitant therapy should be avoided.

Sunitinib: Co-administration of Temsirolimus and Sunitinib may result in serious adverse drug reactions.

Tacrolimus: Temsirolimus may decrease the blood concentration of Tacrolimus. Concomitant therapy may increase the adverse/toxic effects of both agents. Concomitant therapy should be avoided.

Telithromycin: Telithromycin may inhibit the metabolism and clearance of Temsirolimus. Concomitant therapy should be avoided.

Tipranavir: Tipranavir may affect the efficacy/toxicity of Temsirolimus.

Trandolapril: Increased risk of angioedema. Monitor for signs and symptoms of facial and systemic edema and/or erythema.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of temsirolimus and its active metabolite, sirolimus, by decreasing their metabolism. Concomitant therapy should be avoided.