OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO	MOLECULAR FORMULA	STRUCTURE
Telotristat	1033805-28-5	C25-H22-Cl-F3-N6-O3

ANNOTATED BIBLIOGRAPHY

References updated: 07 April 2019

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of therapies for carcinoid syndrome).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 549-68.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; does not discuss telotristat).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway-targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• Kulke MH, O'Dorisio T, Phan A, Bergsland E, Law L, Banks P, Freiman J, et al. Telotristat etiprate, a novel serotonin synthesis inhibitor, in patients with carcinoid syndrome and diarrhea not adequately controlled by octreotide. Endocr Relat Cancer 2014; 21: 705-14. [PMC free article: PMC4295770] [PubMed: 25012985]

  (Among 23 patients with carcinoid syndrome and diarrhea despite somatostatin analogue therapy treated with telotristat [150, 250, 350 or 500 mg] vs placebo 3 times daily for 4 weeks, improvement in diarrhea occurred more frequently with telotristat than placebo [75% vs 20%], while ALT elevations were less common [17% vs 40%] and were less than twice baseline in all).
• Pavel M, Hörsch D, Caplin M, Ramage J, Seufferlein T, Valle J, Banks P, et al. Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial. J Clin Endocrinol Metab 2015; 100: 1511-9. [PubMed: 25636046]

  (Among 15 patients with metastatic neuroendocrine tumors and carcinoid syndrome with diarrhea despite somatostatin analogue therapy treated with telotristat [150 to 500 mg 3 times daily] for 12 weeks, all had some decrease in stool frequency and common side effects were abdominal pain and diarrhea; 1 patient had transient ALT and AST elevations and 1 had GGT elevations, but all were less than twice ULN and none were accompanied by jaundice).
• Telotristat ethyl(Xermelo) for carcinoid syndrome diarrhea. Med Lett Drugs Ther 2017; 59 (1525): 119-20. [PubMed: 28699933]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of telotristat for diarrhea due to carcinoid syndrome shortly after its approval in the US; mentions common adverse events of nausea, headache, depression, flatulence, decreased appetite, edema, fever and GGT elevations, but makes no mention of ALT elevations or hepatotoxicity).
• Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K, Welin S, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 2017; 35: 14-23. [PubMed: 27918724]

  (Among 35 patients with carcinoid syndrome and diarrhea despite somatostatin analogue therapy, response rates in reduction of diarrhea were greater with telotristat [250 mg, 44% and 500 mg, 42%] than placebo [20%] given 3 times daily for 12 weeks, and adverse event rates were similar except for nausea [13% and 31% vs 11%] and ALT [4% vs none] and GGT elevations [9% vs none], but no patient developed clinically apparent liver injury or jaundice).
• Markham A. Telotristat ethyl: first global approval. Drugs 2017; 77: 793-8. [PubMed: 28382568]

  (Review of the structure, mechanism of action, pharmacology, history of development, clinical efficacy and safety of telotristat shortly after its approval in the US; does not mention ALT elevations or hepatotoxicity).
• Pavel M, Gross DJ, Benavent M, Perros P, Srirajaskanthan R, Warner RRP, Kulke MH, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial. Endocr Relat Cancer 2018; 25: 309-22. [PMC free article: PMC5811631] [PubMed: 29330194]

  (Among 76 patients with carcinoid syndrome and inadequate control of diarrhea on somatostatin analogue therapy treated with telotristat [250 mg or 500 mg] or placebo 3 times daily for 12 weeks, a subset of whom continued telotristat therapy [titrated to 500 mg] for 36 weeks, symptoms of diarrhea decreased more with telotristat therapy than placebo while adverse event rates were similar; ALT elevations occurred in 4.5% and GGT elevations in 6% of those on extended therapy, the enzyme elevations not accompanied by jaundice but led to early discontinuation in 2 patients [3%]).
• Anthony LB, Kulke MH, Caplin ME, Bergsland E, Öberg K, Pavel M, Hörsch D, et al. Long-term safety experience with telotristat ethyl across five clinical studies in patients with carcinoid syndrome. Oncologist 2019 Jan 16. [Epub ahead of print] [PMC free article: PMC6693702] [PubMed: 30651397]

  (Among 239 patients with carcinoid syndrome and diarrhea who were treated with telotristat in 5 clinical trials, adverse events were mostly mild-to-moderate in severity and similar in overall rate in patients receiving placebo; ALT elevations not discussed but there were no hepatic serious adverse events).