telotristat ethyl (Rx)

>10%

Nausea (13%)

Headache (11%)

1-10%

Increased GGT (9%)

Depression (9%)

Peripheral edema (7%)

Flatulence (7%)

Decreased appetite (7%)

Pyrexia (7%)

Abdominal pain (5%)

Constipation (5%)

Increased alkaline phosphatase (<5%)

Increased ALT and AST (<5%)

Contraindications

None

Cautions

Reduces bowel movement frequency; monitor for development of constipation and/or severe, persistent, or worsening abdominal pain; discontinue if severe constipation or severe persistent or worsening abdominal pain develops

Drug interaction overview

• Telotristat ethyl induces CYP3A4 and may reduce systemic exposure of sensitive CYP3A4 substrates
• Short-acting octreotide decreases telotristat Cmax and AUC by 79% and 68%, respectively; administer octreotide at least 30 minutes after telotristat ethyl (also see Administration)

Pregnancy

There are no human data in pregnant women to inform a drug-associated risk

Animal studies

• No effects on embryo-fetal development were observed with administration of telotristat ethyl to rats during organogenesis at doses up to 750 mg/kg/day (~9 times the exposure at recommended human dose [RHD])
• Treatment of pregnant rabbits during organogenesis produced maternal toxicity and postimplantation loss at doses of ≥250 mg/kg/day (~15 times the exposure at the RHD), and reduced fetal weight at 500 mg/kg/day (~33 times the exposure at the RHD)

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

If administered to a breastfeeding woman, monitor infant for constipation

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Telotristat, the active metabolite of telotristat ethyl, inhibits tryptophan hydroxylase, which mediates the rate-limiting step in serotonin biosynthesis

Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract, and is overproduced in patients with carcinoid syndrome

In vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl

Absorption

Peak plasma time: 1 hr (telotristat ethyl); 2 hr (telotristat)

Peak plasma concentration: 7 ng/mL (telotristat ethyl); 900 ng/mL (telotristat)

AUC: 22 ng·hr/mL (telotristat ethyl); 3000 ng·hr/mL (telotristat)

Administration with food significantly increases systemic exposure of telotristat ethyl and telotristat

Distribution

Protein bound: >99% (both telotristat ethyl and telotristat)

P-gp substrate

Metabolism

Telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite

Telotristat is further metabolized

Telotristat ethyl and telotristat are not substrates for CYP enzymes

Elimination

Half-life: 0.6 hr (telotristat ethyl); 5 hr (telotristat)

Total clearance: 2.7 L/hr (telotristat ethyl); 152 L/hr (telotristat)

Excretion: <0.4% urine; 92.8% feces

Oral Administration

Take with food

When used in combination with short-acting octreotide, administer short-acting octreotide at least 30 minutes after telotristat ethyl

Discontinue if severe constipation develops

Missed dose

• If a dose is missed, take the next dose at the regular time
• Do not take 2 doses at the same time to make up for a missed dose

Storage

Store at controlled room temperature (25°C [77°F])

Excursions permitted to 15-30°C (59-86°F)