4-[2-Amino-6-[(1R)-1-[4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]-4-pyrimidinyl]-L-phenylalanine ethyl ester

574.98200

574.98

8G388563M7

C150126

A16A

131.17000

6.27010

white solid

1.42g/cm3

Telotristat causes depression and constipation in high doses.

High plasma protein binding of its active metabolite, Telotristat.

As a serotonin synthesis inhibitor, telotristat etiprate, has the potential to reduce serotonin levels and address the key elements of carcinoid syndrome.|Xermelo is indicated for the treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy.

Activity is mainly in the gastrointestinal tract, with minimal effects reported on the brain and cardiovascular system, accompanied by an excellent safety profile. In normal mice, telotristat etiprate (administered once daily for 4 days at doses of 15–300 mg/kg/day) was found to reduce serotonin levels throughout the gastrointestinal tract. These reductions occurred in a dose dependent fashion with maximal effects observed with doses of telotristat etiprate ≥150 mg/kg. No significant change in brain serotonin or 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) was observed. Similar findings were seen in Sprague-Dawley rats. Gastrointestinal motility studies were conducted in rats using the charcoal meal test. There was a significant dose-related delay in both gastrointestinal transit and gastric emptying, associated with a reduction in blood serotonin levels and proximal colon serotonin. A quantitative whole-body autoradiography study was conducted to assess the absorption, distribution and excretion of radioactivity in rats following a single oral dose of telotristat etiprate labeled with carbon 14. Rats were administered either 30 mg/kg or 100 mg/kg of the compound. The distribution of radioactivity was limited to tissues of the hepatic and renal system and the contents of the GI tract. There was no measurable radioactivity in the brain at any dose tested.

Low systemic absorption. Tmax of 2–4 h, supporting the 8-hourly administration|Telotristat ethyl is mainly excreted in feces.|Not available

Metabolized by the liver.

4–12 h

Telotristat etiprate is an ethyl ester prodrug which is hydrolyzed to its active moiety LP-778902 both in vivo and in vitro. Systemic exposure of telotristat etiprate is relatively low, as the hydrolysis to the active moiety is rapid. LP-778902 is a potent inhibitor of TPH with an in vivo IC50 of 0.028 μM. While existing treatments for carcinoid syndrome work to reduce the release of serotonin outside tumor cells, telotristat etiprate works at the source to reduce serotonin production within the tumor cells. By specifically inhibiting serotonin production, telotristat etiprate seeks to control this important driver of carcinoid syndrome and, in turn, provide patients with more control over their disease.

telotristat ethyl

Human drugs -> Orphan -> Xermelo -> EMA Drug Category|Other alimentary tract and metabolism products -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients