Xermelo (telotristat etiprate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Telotristat ethyl is a prodrug of telotristat, which is a tryptophan hydroxylase inhibitor. The drug is commercially available as the hippurate salt, telotristat etiprate.
Telotristat ethyl is a prodrug of telotristat, which is a tryptophan hydroxylase inhibitor. The drug is commercially available as the hippurate salt, telotristat etiprate. Tryptophan hydroxylase is the rate-limiting enzyme in the biosynthesis of serotonin from tryptophan in the GI tract.
Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the GI tract. In carcinoid syndrome, which is a condition associated with overproduction of serotonin, inhibition of tryptophan hydroxylase activity by telotristat and telotristat ethyl reduces the production of peripheral serotonin and thereby the frequency of carcinoid syndrome diarrhea. In vitro, telotristat is 29-fold more potent than telotristat ethyl in its inhibition of the tryptophan hydroxylase enzyme.
Following oral administration, telotristat ethyl is hydrolyzed by carboxylesterases to its active metabolite, telotristat. Telotristat is further metabolized to form a major inactive metabolite, LP-951757; systemic exposure of this metabolite is approximately 35% that of telotristat and approximately 122-fold higher than that of telotristat ethyl. Peak plasma concentrations and area under the concentration-time curve (AUC) of telotristat ethyl and telotristat appear to be proportional to dose following administration of a single dose of the parent drug over the dosage range of 100 mg to 1 g under fasted conditions.
Peak plasma concentrations of telotristat ethyl and telotristat occur within 0.5-2 hours and 1-3 hours, respectively, after oral administration of the parent drug. Accumulation of telotristat ethyl and telotristat is negligible following repeated administration of telotristat ethyl 500 mg 3 times daily. Plasma concentrations of telotristat ethyl and telotristat decline in a biphasic manner.
Oral administration of a single 500-mg dose of telotristat etiprate with a high-fat meal resulted in an increase in peak plasma concentrations of telotristat ethyl and telotristat of 112 and 47%, respectively, and an increase in AUC of 264 and 33%, respectively. Both telotristat ethyl and telotristat are more than 99% bound to plasma proteins. The terminal half-life of telotristat ethyl and telotristat in healthy individuals is approximately 0.6 and 5 hours, respectively.
Following oral administration of a radiolabeled dose of telotristat ethyl, 92.8% of the dose was recovered in feces and less than 0.4% of the dose was recovered in urine. The pharmacokinetics of telotristat do not appear to be affected by age (18-83 years), gender, or body weight (40-115 kg).
USES: This medication is used along with another drug (a somatostatin analog such as octreotide) to treat diarrhea due to carcinoid syndrome. Telotristat helps to reduce the number of bowel movements that you may have.
Generic name: telotristat etiprate
Pronunciation: (tel-OH-tri-stat)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Xermelo
Indications
The following indications are listed for Xermelo:
- Carcinoid Syndrome Diarrhea
Also known as: Diarrhea Co-Occurrent And Due To Carcinoid Syndrome.
Dosing
Telotristat ethyl is commercially available as telotristat etiprate (the hippurate salt of telotristat ethyl); dosage is expressed in terms of telotristat ethyl (the free base).
Telotristat etiprate is administered orally 3 times daily and should be taken with food. (See Description.)
If a dose of telotristat etiprate is missed, patients should not take an extra dose. The next dose should be taken at the regularly scheduled time.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Telotristat ethyl is metabolized by hydrolysis to the active metabolite telotristat by carboxylesterases. Telotristat is further metabolized by decarboxylation and deamination, including to a major inactive metabolite; however, the drug interaction potential of this metabolite is unknown.
In vitro studies indicate that telotristat ethyl and its active metabolite telotristat are not substrates of cytochrome P-450 (CYP) isoenzymes. Telotristat ethyl and telotristat have not been adequately studied in vitro to indicate whether the drug or its active metabolite inhibit CYP isoenzymes 2B6, 2C8, or 2C9 or induce CYP isoenzymes 1A2 or 2B6. Because of limited in vitro data, the effects of telotristat ethyl and telotristat on CYP3A4 are not fully established. (See Substrates of CYP3A4 under Drug Interactions: Drugs Metabolized by Hepatic Microsomal Enzymes.)
In vitro studies indicate that telotristat ethyl inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). In vitro data suggest that telotristat is not an inhibitor of P-gp and BCRP at clinically relevant concentrations, but is a substrate of P-gp.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
The manufacturer states that there are no known contraindications to the use of telotristat ethyl.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 5% or more of patients receiving telotristat ethyl for the management of carcinoid syndrome diarrhea and at an incidence greater than that reported with placebo include nausea, headache, elevated concentrations of gamma-glutamyltransferase (gamma-glutamyltranspeptidase, GGT, GGTP), depression, peripheral edema, flatulence, decreased appetite, pyrexia, abdominal pain, and constipation.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of telotristat ethyl have not been established in pediatric patients.
There are no adequate and well-controlled studies of telotristat ethyl in pregnant women.
Embryotoxicity was not observed in pregnant animals receiving telotristat ethyl at exposure levels equivalent to approximately 5-9 times the human exposure of the active metabolite at the recommended dosage; however, embryotoxicity (i.e., post-implantation loss, decreased fetal weight) and maternal toxicity (i.e., mortality, impaired weight gain) were observed in pregnant animals receiving telotristat ethyl at exposure levels equivalent to approximately 15-33 times the human exposure of the active metabolite at the recommended dosage. Although postnatal development was not affected in rats receiving telotristat ethyl during organogenesis through lactation at exposure levels equivalent to approximately 5 times the human exposure for the active metabolite at the recommended dosage, an increase in pup mortality was observed on postnatal days 0-4.
It is not known whether telotristat ethyl is distributed into milk in humans or animals or whether the drug has any effects on nursing infants and on milk production. In addition, the effects of local GI and systemic exposure to telotristat ethyl in breast-fed infants are unknown. The developmental and health benefits of breast-feeding to the infant should be considered along with the women's clinical need for the drug and any potential adverse effects on the breast-fed infant from telotristat ethyl or from the underlying maternal condition. The manufacturer recommends that breast-fed infants be monitored for symptoms of constipation. (See Constipation under Cautions: Warnings/Precautions.)
In the principal efficacy study evaluating telotristat ethyl for carcinoid syndrome diarrhea, 42% of patients were 65 years of age or older. No overall differences in safety or efficacy were observed between geriatric patients and younger adults in this study. Other reported clinical experience has not identified differences in response between geriatric and younger patients, but greater sensitivity in some older patients cannot be ruled out.
Based on pharmacokinetic analyses, the pharmacokinetics of telotristat do not appear to be affected by age (18-83 years).
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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