Temsirolimus

Temsirolimus
Names
Trade namesTorisel
Other namesCCI-779
IUPAC name
  • (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
Clinical data
Drug classmTOR inhibitor[1]
Main usesRenal cell carcinoma (RCC), mantle cell lymphoma[1][2]
Side effectsPneumonia, low platelets, low red blood cells, high blood sugar, difficulty breathing, vomiting, rash, swelling, tiredness, fever[2]
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		Intravenous
    Typical dose25 to 75 mg once weekly[2]
    External links
    AHFS/Drugs.comMonograph
    US NLMTemsirolimus
    MedlinePlusa607071
    Legal
    License data
    Legal status
    Pharmacokinetics
    MetabolismLiver
    Elimination half-life17.3 hours (temsirolimus); 54.6 hours (sirolimus)[3]
    ExcretionUrine (4.6%), faeces (78%)[3]
    Chemical and physical data
    FormulaC56H87NO16
    Molar mass1030.303 g·mol−1

    Temsirolimus, sold under the brand name Torisel, is a medication used to treat renal cell carcinoma (RCC) and mantle cell lymphoma.[1][2] It is given by gradual injection into a vein.[2] It is generally used together with an antihistamine such as diphenhydramine.[2][1]

    Common side effects include infections such as pneumonia, low platelets, low red blood cells, high blood sugar, difficulty breathing, vomiting, rash, swelling, tiredness, and fever.[2] Serious side effects may include allergies, pulmonary embolism, and high blood fat.[2] It is converted in the body to sirolimus; which works by blocking a protein called mTOR.[1][2]

    Temsirolimus was approved for medical use in the United States and Europe in 2007.[2][1] In the United States it costs about 1,900 USD per 25 mg dose as of 2021.[4] This amount in the United Kingdom costs the NHS about £620.[5]

    Medical uses

    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.[6]

    Dosage

    For renal cell carcinoma a dose of 25 mg per week is generally used.[2]

    For mental cell lymphoma the typically dose is 175 mg per week for three weeks and than 75 mg per week.[2]

    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.[7][8]

    Side effects

    The toxicity profile is based on what was found in the phase III trial.[7]

    • 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.[9]

    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.[10] 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.[8]

    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;[11] therefore, its activity may be more attributed to its metabolite rather than the prodrug itself (despite claims to the contrary by the manufacturer).[12] Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumor angiogenesis by reducing synthesis of VEGF.[13]

    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.[14] 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.[15] Whether or not mTOR kinase is activated, determines whether the tumor cell produces key proteins needed for proliferation, growth, survival, and angiogenesis.[16]

    mTOR is activated in tumor cells by various mechanisms including growth factor surface receptor tyrosine kinases, oncogenes, and loss of tumor suppressor genes. These activating factors are known to be important for malignant transformation and progression.[17] mTOR is particularly important in the biology of 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.[18]

    History

    See also: Discovery and development of mTOR inhibitors

    References

    1. 1 2 3 4 5 6 "Temsirolimus Monograph for Professionals". Drugs.com. Archived from the original on 2 March 2015. Retrieved 25 September 2021.
    2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Torisel EPAR". European Medicines Agency. Archived from the original on 11 November 2020. Retrieved 6 November 2020.
    3. 1 2 Temsirolimus Drug Monograph. CCO Formulary - June 2014: Cancer Care Ontario. p. 2.{{cite book}}: CS1 maint: location (link)
    4. ↑ "Torisel Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 20 April 2021. Retrieved 25 September 2021.
    5. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 1058. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    6. ↑ Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. (May 2007). "Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma". The New England Journal of Medicine. 356 (22): 2271–81. doi:10.1056/NEJMoa066838. PMID 17538086.
    7. 1 2 Bellmunt J, Szczylik C, Feingold J, Strahs A, Berkenblit A (August 2008). "Temsirolimus safety profile and management of toxic effects in patients with advanced renal cell carcinoma and poor prognostic features". Annals of Oncology. 19 (8): 1387–92. doi:10.1093/annonc/mdn066. PMID 18385198.
    8. 1 2 Temsirolimus Drug Monograph. CCO Formulary - June 2014: Cancer Care Ontario. p. 4.{{cite book}}: CS1 maint: location (link)
    9. ↑ Choueiri TK, Je Y, Sonpavde G, Richards CJ, Galsky MD, Nguyen PL, et al. (August 2013). "Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors". Annals of Oncology. 24 (8): 2092–7. doi:10.1093/annonc/mdt155. PMID 23658373. Lay summary – MedPage Today (Feb 17, 2013). {{cite journal}}: Cite uses deprecated parameter |lay-url= (help)
    10. ↑ Duran I, Siu LL, Oza AM, Chung TB, Sturgeon J, Townsley CA, et al. (August 2006). "Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus". European Journal of Cancer. 42 (12): 1875–80. doi:10.1016/j.ejca.2006.03.015. PMID 16806903.
    11. ↑ Hastings, Kenneth. "Pharmacology Review, Application Number 22-088" (PDF). FDA. Archived (PDF) from the original on 4 March 2016. Retrieved 7 March 2015.
    12. ↑ "Temsirolimus Monograph for Professionals". Drugs.com. Drugs.com. Archived from the original on 2 March 2015. Retrieved 7 March 2015.
    13. ↑ Wan X, Shen N, Mendoza A, Khanna C, Helman LJ (May 2006). "CCI-779 inhibits rhabdomyosarcoma xenograft growth by an antiangiogenic mechanism linked to the targeting of mTOR/Hif-1alpha/VEGF signaling". Neoplasia. 8 (5): 394–401. doi:10.1593/neo.05820. PMC 1592447. PMID 16790088.
    14. ↑ Rubio-Viqueira B, Hidalgo M (June 2006). "Targeting mTOR for cancer treatment". Current Opinion in Investigational Drugs. 7 (6): 501–12. PMID 16784020.
    15. ↑ Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. (October 2002). "Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin". Molecular and Cellular Biology. 22 (20): 7004–14. doi:10.1128/MCB.22.20.7004-7014.2002. PMC 139825. PMID 12242281.
    16. ↑ Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (June 2006). "Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus". Cancer Research. 66 (11): 5549–54. doi:10.1158/0008-5472.CAN-05-2825. PMID 16740688.
    17. ↑ Dancey JE (September 2006). "Therapeutic targets: MTOR and related pathways". Cancer Biology & Therapy. 5 (9): 1065–73. doi:10.4161/cbt.5.9.3175. PMID 16969122.
    18. ↑ Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, et al. (January 2006). "Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer". Nature Medicine. 12 (1): 122–7. doi:10.1038/nm1337. PMID 16341243. S2CID 1853822.
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