Telotristat

Telotristat
Names
Trade namesXermelo
Other namesTelotristat ethyl, LX1032, LX1606
IUPAC name
  • [(S)-Ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate]
Clinical data
Main usesDiarrhea due to carcinoid syndrome[1]
Side effectsAbdominal pain, liver problems, tiredness[2]
Pregnancy
category
  • AU: B3
  • US: N (Not classified yet)
    Routes of
    use    		By mouth (tablets)
    Typical dose250 mg TID[1]
    External links
    AHFS/Drugs.comMonograph
    US NLMTelotristat
    MedlinePlusa617029
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only [3]
    • EU: Rx-only [2]
    Pharmacokinetics
    Protein binding>99% (both telotristat ethyl and telotristat)
    MetabolismHydrolysis via carboxylesterases
    MetabolitesTelotristat
    Elimination half-life0.6 hours (telotristat ethyl), 5 hours (telotristat)
    ExcretionFeces (92.8%), urine (less than 0.4%)[3]
    Chemical and physical data
    FormulaC27H26ClF3N6O3
    Molar mass574.99 g·mol−1
    3D model (JSmol)
    SMILES
    • CCOC(=O)C(CC1=CC=C(C=C1)C2=CC(=NC(=N2)N)OC(C3=C(C=C(C=C3)Cl)N4C=CC(=N4)C)C(F)(F)F)N
    InChI
    • InChI=1S/C27H26ClF3N6O3/c1-3-39-25(38)20(32)12-16-4-6-17(7-5-16)21-14-23(35-26(33)34-21)40-24(27(29,30)31)19-9-8-18(28)13-22(19)37-11-10-15(2)36-37/h4-11,13-14,20,24H,3,12,32H2,1-2H3,(H2,33,34,35)/t20-,24+/m0/s1
    • Key:MDSQOJYHHZBZKA-GBXCKJPGSA-N

    Telotristat, sold under the brand name Xermelo, is a medication used to treat diarrhea due to carcinoid syndrome.[1] It is taken by mouth, three times per day.[1] It is used together with a somatostatin like agent.[1]

    Common side effects include abdominal pain, liver problems, and tiredness.[2] Other side effects may include constipation.[1] Smaller doses may be required in those with liver problems.[2] Use during pregnancy is not recommended.[4] It works by blocking tryptophan hydroxylase, thereby decreasing the production of serotonin.[1][2]

    Telotristat was approved for medical use in the United States and Europe in 2017.[1][2] In the United States it costs about 8,000 USD per month as of 2021.[5] This amount in the United Kingdom costs the NHS about £1,100.[4]

    Medical uses

    Telotristat is used in combination with somatostatin analog (SSA) therapy for the treatment of adults with diarrhea associated with carcinoid syndrome that SSA therapy alone has inadequately controlled.[6][7]

    Dosage

    It is generally take three times per day at a dose of 250 mg.[1] Smaller doses may be required in those with liver problems.[2]

    Side effects

    Common adverse effects noted in clinical trials include nausea, headache, elevated liver enzymes, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decreased appetite, and fever. Constipation is also common, and may be serious or life-threatening (especially in overdose).[6]

    Pharmacology

    Telotristat is an inhibitor of tryptophan hydroxylase,[8] which mediates the rate-limiting step in serotonin biosynthesis.[3] It is formulated as telotristat etiprate — a hippurate salt of telotristat ethyl.[3]

    Action of telotristat on tryptophan hydroxylase

    History

    The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[9]

    Society and culture

    Formulations

    It is marketed by Lexicon Pharmaceuticals (as telotristat etiprate). 328 mg telotristat etiprate is equivalent to 250 mg telotristate ethyl.[3]

    Telotristat etiprate

    References

    1. 1 2 3 4 5 6 7 8 9 "Telotristat Monograph for Professionals". Drugs.com. Archived from the original on 5 March 2021. Retrieved 25 September 2021.
    2. 1 2 3 4 5 6 7 "Xermelo EPAR". European Medicines Agency (EMA). Archived from the original on 29 December 2019. Retrieved 17 April 2020.
    3. 1 2 3 4 5 "Xermelo- telotristat ethyl tablet". DailyMed. 30 October 2020. Archived from the original on 12 November 2020. Retrieved 11 November 2020.
    4. 1 2 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 938. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    5. ↑ "Xermelo Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 11 July 2021. Retrieved 25 September 2021.
    6. 1 2 "FDA Approves Xermelo for Carcinoid Syndrome Diarrhea" (Press release). U.S. Food and Drug Administration (FDA). February 28, 2017. Archived from the original on 11 December 2019. Retrieved 1 March 2017.
    7. ↑ "Xermelo (telotristat ethyl) Tablets". U.S. Food and Drug Administration (FDA). 4 April 2017. Archived from the original on 14 September 2019. Retrieved 17 April 2020.
    8. ↑ Kulke M, Hörsch D, Caplin M, Anthony L, Bergsland E, Oberg K, et al. (1 October 2016). "Integrated Placebo-Controlled Safety Analysis from Clinical Studies of Telotristat Ethyl for the Treatment of Carcinoid Syndrome". Annals of Oncology. 27 (6): 136–48. doi:10.1093/annonc/mdw369.07.
    9. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
    Identifiers:
    • "Telotristat ethyl". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-08-29. Retrieved 2021-07-01.
    • "Telotristat etiprate". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-08-29. Retrieved 2021-07-01.
    • Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, et al. (October 2014). "Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide". Endocrine-Related Cancer. 21 (5): 705–14. doi:10.1530/ERC-14-0173. PMC 4295770. PMID 25012985.
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