Telotristat Ethyl

Telotristat ethyl is a prodrug. After oral intake it is rapidly hydrolysed by carboxylesterases to telotristat, its active metabolite, which is more than 25 times more active than the prodrug. Both inhibit the enzymes that make serotonin. Serotonin regulates secretion, motility, inflammation and sensation in the gut and is over-secreted in carcinoid syndrome, which is why the condition causes diarrhoea. Telotristat ethyl is used together with somatostatin analogue (SSA) therapy, not in place of it. Xermelo is listed by the EMA as an orphan medicine, that is, a medicine for a rare disease.

Mechanism of Action

• Tryptophan hydroxylase inhibition: telotristat ethyl and telotristat inhibit the L-tryptophan hydroxylases TPH1 and TPH2, the rate-limiting steps in serotonin biosynthesis.
• Peripheral effect: by inhibiting peripheral TPH1, telotristat reduces serotonin production and so eases the symptoms of carcinoid syndrome. Animal studies found no change in brain serotonin and no radioactivity in the brain.
• Biomarker effects: in phase 1 studies in healthy volunteers (100 mg once daily up to 500 mg three times daily), telotristat ethyl significantly lowered whole-blood serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA) compared with placebo. In patients with carcinoid syndrome, 250 mg three times daily significantly lowered u5-HIAA compared with placebo in both phase 3 studies.
• Clinical evidence: the pivotal TELESTAR trial was a 12-week, double-blind, placebo-controlled, randomised phase 3 study in adults with metastatic neuroendocrine tumours receiving SSA therapy (135 patients evaluated; mean age 64 years), followed by a 36-week open-label extension. The results are given in SmPC section 5.1.

Pharmacokinetics

• Absorption: rapid, with almost complete conversion to telotristat. Peak plasma levels are reached after 0.53–2.00 hours for telotristat ethyl and 1.50–3.00 hours for telotristat. After a single fasted 500 mg dose (twice the recommended dose) in healthy subjects, mean Cmax and AUC0-inf were 4.4 ng/mL and 6.23 ng·h/mL for telotristat ethyl and 610 ng/mL and 2,320 ng·h/mL for telotristat. Variability in patients is high (coefficient of variation 18–99%), and steady state is reached at or before week 24. A slight accumulation was seen at 250 mg three times daily (median accumulation ratio 1.55, with high variability between patients).
• Food effect: a high-fat meal raised exposure to telotristat ethyl (Cmax 112%, AUC0-tlast 272% and AUC0-inf 264% higher) and to telotristat (47%, 32% and 33% higher), which is why the tablets are taken with food.
• Distribution: both telotristat ethyl and telotristat are more than 99% bound to plasma proteins.
• Metabolism: hydrolysis by carboxylesterases to telotristat, the active and major metabolite. The only other metabolite above 10% of total plasma drug-related material is an oxidative decarboxylated deaminated metabolite (LP-951757), with about 35% of the exposure to telotristat and no pharmacological activity at TPH1 in vitro.
• Elimination: after a single radiolabelled 500 mg dose about 93% was recovered, mostly in the faeces; less than 1% appeared in urine, and the renal clearance of telotristat is 0.126 L/h. The apparent half-life is about 0.6 hours for telotristat ethyl and 5 hours for telotristat; after 500 mg three times daily the terminal half-life is about 11 hours.
• Special populations: the effect of age has not been conclusively evaluated, and no study was done in the elderly. In severe to moderate renal impairment not needing dialysis, peak exposure to telotristat ethyl rose 1.3-fold and exposure to telotristat by less than 1.52-fold, with no clinically meaningful change in profile or safety. In hepatic impairment, after a single 500 mg dose, exposure to telotristat ethyl and telotristat was 2.3- and 2.4-fold higher in mild and 3.2- and 3.5-fold higher in moderate impairment; in severe impairment (single 250 mg dose) exposure was several-fold higher, and the half-life of telotristat rose from 5.47 to 16.0 hours.

• Carcinoid syndrome diarrhoea: treatment of carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. Carcinoid syndrome occurs in patients with metastatic neuroendocrine tumours and involves over-secretion of serotonin.

• Hypersensitivity to the active substance or to any of the excipients.

The reactions below come from a pooled safety dataset of 70 patients with carcinoid syndrome who took telotristat ethyl 250 mg three times daily with SSA therapy in placebo-controlled studies. The most common were abdominal pain (26%), increased gamma-glutamyltransferase (11%) and fatigue (10%), generally of mild or moderate intensity. Abdominal pain was also the reaction most often leading to discontinuation (7.1% of patients, 5 of 70).

Very common (≥1/10): abdominal pain (upper and lower), nausea, increased gamma-glutamyltransferase, fatigue.

Common (≥1/100 to <1/10): decreased appetite; depression, depressed mood; headache; abdominal distension, constipation, flatulence; increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP); peripheral oedema, pyrexia.

Uncommon (≥1/1,000 to <1/100): faecaloma (observed only in a study at 500 mg three times daily, twice the recommended dose), intestinal obstruction.

Rises in ALT above 3 times the upper limit of normal, or in ALP above 2 times the upper limit, have been reported, mostly at the higher 500 mg dose and without a rise in total bilirubin. Depression and constipation are covered under Special Instructions.

• Short-acting octreotide: markedly lowers exposure to telotristat ethyl and telotristat (in healthy volunteers, Cmax and AUC of telotristat ethyl fell by 86% and 81%). If short-acting octreotide is needed, give it at least 30 minutes after telotristat ethyl. Reduced exposure was not seen in patients on long-acting SSA therapy in the 12-week study.
• Carboxylesterase 2 (CES2) inhibitors: loperamide inhibits the CES2 metabolism of telotristat ethyl in vitro, but in phase 3 studies the two were routinely combined with no safety concerns.
• CYP2B6 substrates (for example valproic acid, bupropion, sertraline): telotristat induced CYP2B6 in vitro and may lower their exposure and efficacy; monitor for suboptimal efficacy.
• CYP3A4 substrates (for example midazolam, everolimus, sunitinib, simvastatin, ethinyloestradiol, amlodipine, ciclosporin): may have lower exposure and efficacy. In a study with a sensitive CYP3A4 substrate, 5 days of telotristat ethyl 500 mg three times daily cut the substrate’s AUC by 48%. Monitor for suboptimal efficacy.
• CES2 substrates (for example prasugrel, irinotecan, capecitabine, flutamide): exposure may change; if co-administration is unavoidable, monitor for suboptimal efficacy and adverse reactions.
• Acid reducers (omeprazole, famotidine): raised the AUC of telotristat ethyl 2–3-fold without changing that of telotristat, so no dose adjustment is needed.
• Food: take with food; a high-fat meal increases exposure.

Telotristat ethyl is taken by mouth with food.

Recommended Dose

• 250 mg three times daily.
• A clinical response is usually reached within 12 weeks; the benefit of continued treatment should be reassessed in a patient who has not responded in that time.
• Higher doses are not recommended: because of the high variability between patients, accumulation in some patients cannot be excluded.

Special Populations

• Elderly: no specific dose recommendation.
• Renal impairment: no dose change in mild, moderate or severe impairment when dialysis is not needed; as a precaution, patients with severe impairment are monitored for reduced tolerability. Not recommended in end-stage renal disease requiring dialysis (eGFR below 15 mL/min), because efficacy and safety have not been established.
• Hepatic impairment: in mild impairment (Child-Pugh A) the dose may need to be reduced to 250 mg twice daily according to tolerability; in moderate impairment (Child-Pugh B), to 250 mg once daily. Not recommended in severe impairment (Child-Pugh C).
• Children and adolescents: there is no relevant use in the paediatric population for carcinoid syndrome.

Missed Dose

Take the next dose at the next scheduled time. Do not take a double dose to make up for a missed one.

Hepatic Enzyme Elevations

Liver enzymes rose in clinical studies. Laboratory monitoring before and during treatment is recommended as clinically indicated, and patients with hepatic impairment need continuous monitoring for adverse reactions and worsening liver function. A patient with symptoms suggesting liver dysfunction should have liver enzymes tested, and telotristat should be stopped if liver injury is suspected. It should not be restarted unless the injury can be explained by another cause.

Constipation

Telotristat reduces the frequency of bowel movements, and constipation was reported at the higher 500 mg dose. Patients should be monitored for signs and symptoms of constipation. If it develops, the use of telotristat and of other therapies affecting bowel motility should be re-evaluated.

Depressive Disorders

Depression, depressed mood and decreased interest have been reported in clinical studies and after marketing. Patients should tell their doctor about any such symptoms.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should use adequate contraception during treatment.
• Pregnancy: there are no data in pregnant women, and animal studies showed reproductive toxicity. Telotristat ethyl is not recommended in pregnancy or in women of childbearing potential who are not using contraception.
• Breastfeeding: it is unknown whether telotristat ethyl or its metabolite passes into breast milk, and a risk to the infant cannot be excluded. It should not be used during breastfeeding.
• Fertility: no studies in humans; no effect on fertility was seen in animals.

Lactose and Sodium

Each tablet contains 168 mg of lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. The tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Telotristat has a minor influence on the ability to drive and use machines. Fatigue may occur, and patients with fatigue should not drive or use machines until it has passed.

Xermelo tablets need no special storage conditions. They are supplied in PVC/PCTFE/PVC/aluminium blisters in a carton (packs of 90 and 180 tablets; not all pack sizes may be marketed). Keep out of the sight and reach of children.

5 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Xermelo is a tablet taken at home, so it is supplied to the patient or to the treating clinic on prescription.