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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 ®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.

Pharmacodynamics

Effects on Electrocardiogram There were no clinically relevant QT changes observed at the recommended dose for TORISEL (temsirolimus injection) . In a randomized, crossover study, 58 healthy subjects received TORISEL (temsirolimus injection) 25 mg, placebo, and a single oral dose of moxifloxacin 400 mg. A supratherapeutic TORISEL (temsirolimus injection) dose was not studied in this randomized QT trial. The largest difference between the upper bound 2-sided 90% CI for the mean difference between TORISEL (temsirolimus injection) and placebo-corrected QT interval was less than 10 ms. In a different trial in 69 patients with a hematologic malignancy, TORISEL (temsirolimus injection) doses up to 175 mg were studied. No patient with a normal QTcF at baseline had an increase in QTcF > 60 ms. Additionally, there were no patients with a QTcF interval greater than 500 ms.

Pharmacokinetics

Absorption

Following administration of a single 25 mg dose of TORISEL in patients with cancer, mean temsirolimus Cmax in whole blood was 585 ng/mL (coefficient of variation, CV =14%), and mean AUC in blood was 1627 ng•h/mL (CV=26%). Typically Cmax occurred at the end of infusion. Over the dose range of 1 mg to 25 mg, temsirolimus exposure increased in a less than dose proportional manner while sirolimus exposure increased proportionally with dose. Following a single 25 mg intravenous dose in patients with cancer, sirolimus AUC was 2.7-fold that of temsirolimus AUC, due principally to the longer half-life of sirolimus.

Distribution

Following a single 25 mg intravenous dose, mean steady-state volume of distribution of temsirolimus in whole blood of patients with cancer was 172 liters. Both temsirolimus and sirolimus are extensively partitioned into formed blood elements.

Metabolism

Cytochrome P450 3A4 is the major isozyme responsible for the formation of five temsirolimus metabolites. Sirolimus, an active metabolite of temsirolimus, is the principal metabolite in humans following intravenous treatment. The remainder of the metabolites account for less than 10% of radioactivity in the plasma. In human liver microsomes temsirolimus was an inhibitor of CYP2D6 and 3A4. However, there was no effect observed in vivo when temsirolimus was administered with desipramine (a CYP2D6 substrate), and no effect is anticipated with substrates of CYP3A4 metabolism.

Elimination

Elimination is primarily via the feces. After a single IV dose of [14C]-temsirolimus approximately 82% of total radioactivity was eliminated within 14 days, with 4.6% and 78% of the administered radioactivity recovered in the urine and feces, respectively. Following a single 25 mg dose of TORISEL in patients with cancer, temsirolimus mean (CV) systemic clearance was 16.2 (22%) L/h. 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.

Effects of Age and Gender

In population pharmacokinetic-based data analyses, no relationship was apparent between drug exposure and patient age or gender.

Clinical Studies

A phase 3, multi-center, three-arm, randomized, open-label study was conducted in previously untreated patients with advanced renal cell carcinoma (clear cell and non-clear cell histologies).

The objectives were to compare Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), and safety in patients receiving IFN-α to those receiving TORISEL (temsirolimus injection) or TORISEL (temsirolimus injection) plus IFN-α. Patients in this study had 3 or more of 6 pre-selected prognostic risk factors (less than one year from time of initial RCC diagnosis to randomization, Karnofsky performance status of 60 or 70, hemoglobin less than the lower limit of normal, corrected calcium of greater than 10 mg/dL, lactate dehydrogenase > 1.5 times the upper limit of normal, more than one metastatic organ site). Patients were stratified for prior nephrectomy status within three geographic regions and were randomly assigned (1:1:1) to receive IFN-α alone (n=207), TORISEL (temsirolimus injection) alone (25 mg weekly; n=209), or the combination arm (n=210).

The ITT population for this interim analysis included 626 patients. Demographics were comparable between the three treatment arms with regard to age, gender, and race. The mean age of all groups was 59 years (range 23-86). Sixty-nine percent were male and 31% were female. The racial distribution for all groups was 91% White, 4% Black, 2% Asian, and 3% other. Sixty-seven percent of patients had a history of prior nephrectomy.

The median duration of treatment in the TORISEL (temsirolimus injection) arm was 17 weeks (range 1-126 weeks). The median duration of treatment on the IFN arm was 8 weeks (range 1-124 weeks).

There was a statistically significant improvement in OS (time from randomization to death) in the TORISEL (temsirolimus injection) 25 mg arm compared to IFN-α. The combination of TORISEL (temsirolimus injection) 15 mg and IFN-α did not result in a significant increase in overall survival when compared with IFN-α alone. Figure 1 is a Kaplan-Meier plot of OS in this study. The evaluations of PFS (time from randomization to disease progression or death) and ORR, were based on blinded independent radiologic assessment of tumor response. Efficacy results are summarized in Table 4.

Table 4: Summary of Efficacy Results of TORISEL (temsirolimus injection) vs. IFN-α

Figure 1: Kaplan-Meier Curves for Overall Survival – TORISEL (temsirolimus injection) vs. IFN

REFERENCES

1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.

2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html

3. American Society of Health-System Pharmacists. (2006) ASHP Guidelines on Handling Hazardous Drugs. Am J Health-syst Pharm. (2006) 63:1172-1193.

4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 8/5/2010
This monograph has been modified to include the generic and brand name in many instances.