Temsirolimus is an inhibitor of cell proliferation and anticancer agent that is used as treatment of advanced renal cell cancer. Temsirolimus therapy is frequently associated with mild serum enzyme elevations, but has yet to be linked to instances of clinically apparent liver injury with jaundice.
Temsirolimus (tem" sir oh' li mus) is an ester of sirolimus, both of which bind to the same intracellular receptor as tacrolimus and cyclosporine, but which block the "mammalian target of rapamycin" (mTOR) rather than calcineurin. mTOR is a serine/threonine kinase which plays an important role in signaling pathways of several cytokines and growth factors, which are involved in carcinogenesis and cancer progression. Inhibition of mTOR causes a decrease in protein synthesis and cell cycle arrest. Temsirolimus therapy has been shown to inhibit progression and prolong survival in patients with advanced and metastatic renal cell cancer. Temsirolimus was approved for use in the United States in 2007 and current indications are limited to therapy of advanced renal cell cancer. Temsirolimus is being actively investigated as therapy of other solid tumors. Temsirolimus is available as liquid solution for injection in vials of 25 mg/mL under the brand name of Torisel. The recommended dose is 25 mg intravenously once weekly until disease progression or unacceptable toxicity. Temsirolimus has many, largely dose dependent, side effects including hypersensitivity reactions, oral ulcers, diarrhea, nausea, poor appetite, fatigue, peripheral edema, rash, anemia and interstitial pneumonitis.
Serum aminotransferase elevations occur in 30% to 40% and alkaline phosphatase in 60% to 70% of patients receiving temsirolimus, but the abnormalities are usually mild, asymptomatic and self-limiting, rarely requiring dose modification or discontinuation. Elevations of liver enzymes above 5 times the upper limit of normal occur in only 2% to 3% of patients. Temsirolimus, like sirolimus, is immunosuppressive and therapy is likely to be associated with episodes of reactivation of hepatitis B, which can be severe and even fatal. Reverse seroconversion (development of HBsAg in a person with preexisting antibody to hepatitis B, either anti-HBs or anti-HBc) has not been reported. Idiosyncratic, clinically apparent acute liver injury has not been linked to temsirolimus therapy, but the total number of patients treated with this drug is limited. Thus, acute liver injury with jaundice due to temsirolimus is probably quite rare, if it occurs at all. Hypersensitivity reactions to temsirolimus infusions are not uncommon (for which reason premedication with an antihistamine is recommended) and instances of Stevens Johnson syndrome have been reported.
Mechanism of Injury
Temsirolimus undergoes extensive hepatic metabolism, largely via the cytochrome P450 system (CYP 3A4). Liver injury might be due to a direct effect of temsirolimus or to a toxic intermediate of its metabolism. Temsirolimus is prone to drug-drug interactions if used with inhibitors or inducers of the cytochrome P450 drug metabolizing enzymes.
Outcome and Management
Acute, symptomatic liver injury associated with temsirolimus therapy has not been described, and the serum enzyme elevations associated with its use are usually mild and transient, resolving spontaneously or with dose modification. Because temsirolimus can lead to reactivation of chronic hepatitis B, routine screening of patients for HBsAg before starting therapy is advisable. Patients who develop reactivation should be treated with an oral nucleoside analogue with potent activity against hepatitis B (entecavir or tenofovir). Temsirolimus is an ester of and partially metabolized to sirolimus and cross sensitivity to adverse effects between these two agents is likely. Whether such cross sensitivity extends to other inhibitors of mTOR (such as everolimus) or calcineurin (cyclosporine, tacrolimus) is not known.
Drug Class: Antineoplastic Agents, Miscellaneous; Transplant Drugs
Other Drugs with Similar Intracellular Actions: Cyclosporine, Everolimus, Mycophenolate, Sirolimus, Tacrolimus, Temsirolimus
Temsirolimus – Torisel®
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