Temsirolimus

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Temsirolimus
Clinical data
Trade namesTorisel
Other namesCCI-779
AHFS/Drugs.comMonograph
MedlinePlusa607071
License data
Pregnancy
category
  • AU: D
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
Elimination half-life17.3 hours (temsirolimus); 54.6 hours (sirolimus)[2]
ExcretionUrine (4.6%), faeces (78%)[2]
Identifiers
  • (1R,2R,4S)-4-{(2R)-2-[(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-1,5,11,28,29-pentaoxo-1,4,5,6,9,10,11,12,13,14,21,22,23,24,25,26,27,28,29,31,32,33,34,34a-tetracosahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontin-3-yl]propyl}-2-methoxycyclohexyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate
ECHA InfoCard
100.211.882 Edit this at Wikidata
Chemical and physical data
FormulaC56H87NO16
Molar mass1030.303 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Temsirolimus, sold under the brand name Torisel, is an intravenous drug for the treatment of renal cell carcinoma (RCC), developed by Wyeth Pharmaceuticals and approved by the U.S. Food and Drug Administration (FDA) in May 2007,[3] and was also approved by the European Medicines Agency (EMA) in November 2007.[1] It is a derivative and prodrug of sirolimus.

Mechanism of action

Temsirolimus is a specific inhibitor of

mTOR and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumor cells. Though temsirolimus shows activity on its own, it is also known to be converted to sirolimus (rapamycin) in vivo;[4] therefore, its activity may be more attributed to its metabolite rather than the prodrug itself (despite claims to the contrary by the manufacturer).[5] Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of VEGF.[6]

mTOR (

mammalian target of rapamycin) is a kinase enzyme inside the cell that collects and interprets the numerous and varied growth and survival signals received by tumor cells.[7] When the kinase activity of mTOR is activated, its downstream effectors, the synthesis of cell cycle proteins such as cyclin D and hypoxia-inducible factor-1a (HIF-1a) are increased. HIF-1a then stimulates VEGF.[8] Whether or not mTOR kinase is activated, determines whether the tumor cell produces key proteins needed for proliferation, growth, survival, and angiogenesis.[9]

mTOR is activated in tumor cells by various mechanisms including growth factor surface receptor tyrosine kinases,

renal cancer (RCC) owing to its function in regulating HIF-1a levels. Mutation or loss of the von Hippel Lindau tumor-suppressor gene is common in RCC and is manifested by reduced degradation of HIF-1a. In RCC tumors, activated mTOR further exacerbates accumulation of HIF-1a by increasing synthesis of this transcription factor and its angiogenic target gene products.[11]

Efficacy

In an international three-arm phase III study with 626 previously untreated, poor-prognosis patients, temsirolimus, interferon-α and the combination of both agents was compared. Median overall survival improved significantly in the temsirolimus group (10.9 months) compared with interferon-α group (7.3 months) and the combination group (8.4 months). Further studies are needed to determine the role of temsirolimus in the first-line treatment of patients with a more favorable prognosis, how it can be combined with other targeted agents and as sequential therapy with sunitinib or sorafenib.[12]

Adverse reactions

The toxicity profile is based on what was found in the phase III trial.[13]

  • adverse reaction
  • hematologic abnormalities
  • laboratory abnormalities
    • triglycerides increased
    • glucose increased
    • phosphorus decreased

Temsirolimus has been generally well tolerated in clinical settings by patients with advanced RCC. In patients with RCC, the adverse effect profile of temsirolimus is primarily metabolic in nature, with minimal impact on QoL compared with the commonly seen side-effects with oral multikinase inhibitors. Temsirolimus' high level of specificity for mTOR likely contributes to the tolerability of temsirolimus. However, temsirolimus increases mortality in cancer patients.[14]

Lung toxicity

Temsirolimus is associated with lung toxicity, and the risk of developing this complication may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.[15] The risk of interstitial lung disease is increased with temsirolimus doses greater than 25 mg, symptoms of which may include dry cough, fever, eosinophilia, chest pain, and dyspnea on exertion. Toxicity usually occurred early (within days to weeks) or late (months to years) after treatment.[16]

Dosing

Although infusion reactions can occur while temsirolimus is being administered, most hypersensitivity reactions occurring on the same day as temsirolimus administration were not severe. Antihistamine pretreatment (e.g. 25–50 mg diphenhydramine, 30 minutes prior to administration) is recommended to minimize the risk of an allergic reaction.[13][16]

See also

  • Discovery and development of mTOR inhibitors

References

  1. ^ a b "Torisel EPAR". European Medicines Agency. 17 September 2018. Retrieved 6 November 2020.
  2. ^ a b Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 2.
  3. ^ "FDA Approves New Drug for Advanced Kidney Cancer" (Press release). U.S. Food and Drug Administration (FDA). May 30, 2007. Archived from the original on October 16, 2012. Retrieved October 15, 2013.
  4. ^ Hastings, Kenneth. "Pharmacology Review, Application Number 22-088" (PDF). FDA. Retrieved 7 March 2015.
  5. ^ "Temsirolimus Monograph for Professionals". Drugs.com. Retrieved 7 March 2015.
  6. PMID 16790088
    .
  7. PMID 16784020
    .
  8. PMID 12242281
    .
  9. PMID 16740688
    .
  10. PMID 16969122
    .
  11. S2CID 1853822
    .
  12. PMID 17538086
    .
  13. ^
    PMID 18385198
    .
  14. PMID 23658373
    .
  15. PMID 16806903
    .
  16. ^ a b Temsirolimus Drug Monograph. Cancer Care Ontario. June 2014. p. 4.

External links

  • "Temsirolimus". Drug Information Portal. U.S. National Library of Medicine.
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