Introduction
Xermelo (telotristat ethyl) is an oral tryptophan hydroxylase inhibitor approved for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults who have an inadequate response to SSA therapy alone. It represents a novel approach to managing this challenging aspect of neuroendocrine tumors.
Mechanism of Action
Xermelo works by inhibiting tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis. Specifically, it targets peripheral TPH (primarily in the gastrointestinal tract) rather than central TPH in the brain. By reducing peripheral serotonin production, Xermelo decreases the excessive serotonin that drives carcinoid syndrome diarrhea without significantly affecting central serotonin levels that regulate mood and cognition.
Indications
Xermelo is indicated for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog therapy in adults inadequately controlled by somatostatin analog monotherapy.
Dosage and Administration
- Standard adult dosage: 250 mg orally three times daily with food
- Administration: Should be taken with food to enhance absorption
- Special populations:
- Renal impairment: No dosage adjustment necessary - Hepatic impairment: Use with caution in moderate to severe impairment - Elderly: No specific dosage adjustment recommended - Pediatrics: Safety and effectiveness not established
Pharmacokinetics
- Absorption: Peak plasma concentrations achieved within approximately 0.5-2 hours
- Distribution: Extensive protein binding (>99%)
- Metabolism: Hydrolyzed to active metabolite telotristat (EPR-100) by carboxylesterases; further metabolized via glucuronidation and oxidation
- Elimination: Primarily fecal excretion (93.5%), with minimal renal excretion (0.5%)
- Half-life: Telotristat ethyl: ~0.6 hours; Active metabolite: ~5 hours
Contraindications
- Hypersensitivity to telotristat ethyl or any component of the formulation
- Concomitant use with strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's wort)
Warnings and Precautions
- Hepatic impairment: Use with caution in patients with moderate to severe hepatic impairment
- Depression: Monitor for new or worsening depression, as serotonin plays a role in mood regulation
- Constipation: May cause constipation, which can be severe; monitor and manage appropriately
- Pregnancy: Use only if potential benefit justifies potential risk to fetus
- Lactation: Advise women not to breastfeed during treatment
Drug Interactions
- Strong CYP3A4 inducers: Contraindicated due to significantly reduced Xermelo exposure
- CYP3A4 substrates: May increase exposure to drugs metabolized by CYP3A4
- OCT2 substrates: May increase exposure to drugs transported by OCT2
- Serotonergic drugs: Theoretical potential for serotonin syndrome, though not reported clinically
Adverse Effects
Common adverse reactions (≥5%):- Nausea (13%)
- Headache (10%)
- Increased gamma-glutamyl transferase (9%)
- Depression (7%)
- Peripheral edema (7%)
- Flatulence (7%)
- Decreased appetite (6%)
- Pyrexia (6%)
- Constipation (5%)
- Depression
- Severe constipation
- Hepatic transaminase elevations
Monitoring Parameters
- Efficacy: Bowel movement frequency, stool consistency, flushing episodes
- Safety: Liver function tests (baseline and periodically)
- Mental health: Assessment for depression or mood changes
- Constipation: Monitor bowel function and manage proactively
- Serum serotonin levels: May be monitored to assess biochemical response
Patient Education
- Take Xermelo exactly as prescribed, three times daily with food
- Do not stop taking your somatostatin analog therapy unless instructed by your healthcare provider
- Report any new or worsening depression, anxiety, or mood changes
- Inform your healthcare provider about all medications you're taking, including over-the-counter drugs and supplements
- Report severe constipation or abdominal pain
- Regular follow-up appointments are important for monitoring safety and effectiveness
- Inform all healthcare providers that you are taking Xermelo
- Do not breastfeed while taking this medication
References
1. Kulke MH, Hörsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35(1):14-23. 2. Xermelo [package insert]. Lexington, MA: Lexicon Pharmaceuticals, Inc.; 2023. 3. Pavel M, Gross DJ, Benavent M, et al. Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELESTAR study. Endocr Relat Cancer. 2018;25(3):309-322. 4. FDA Approval Letter: NDA 208794. February 28, 2017. 5. Anthony L, Ervin C, Lapuerta P, et al. Understanding the patient experience with carcinoid syndrome: exit interviews from a randomized, placebo-controlled study of telotristat ethyl. Patient. 2017;10(6):769-777.