telotristat ethyl
Telotristat ethyl
Generic Name
Telotristat ethyl
Mechanism
- Selective TPH‑1 inhibition: Reduces peripheral conversion of tryptophan to 5‑hydroxytryptophan, the precursor of serotonin.
- Decreases circulating serotonin: By lowering serotonin, telotristat decreases gut motility and secretory diarrhea, and it reduces flushing episodes.
- Minimal central nervous system penetration: Its peripheral selectivity limits CNS side‑effects compared with non‑selective TPH inhibitors.
Pharmacokinetics
| Parameter | Details |
| Formulation | Prodrug (telotristat ethyl) → active metabolite telotristat |
| Absorption | Oral, peak plasma ~2 h after dosing; food increases bioavailability ~50 % |
| Metabolism | Hydrolysis of ethyl ester followed by CYP3A4‑mediated oxidation to telotristat |
| Elimination | Half‑life of telotristat ~7 h; 80 % fecal, 18 % renal |
| Drug Interactions | Strong CYP3A4 inhibitors/inducers alter exposure; avoid strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) |
| Special Populations | No dose adjustment in renal impairment; caution in severe hepatic impairment – contraindicated |
Indications
- Refractory carcinoid‑syndrome diarrhea (≥3 bowel movements/day)
- Refractory carcinoid flushing
- Use as adjunct to approved long‑acting somatostatin analogues (octreotide, lanreotide)
Contraindications
- Contraindicated: Severe hepatic impairment (Child‑Pugh C); hypersensitivity to drug or excipients.
- Warnings
- Hepatotoxicity: Monitor LFTs; discontinue if AST/ALT >3× ULN.
- Potential for carcinoid crisis: Rare; close monitoring if severe flare.
- Drug interactions: Avoid strong CYP3A4 inhibitors/inducers.
- Pregnancy: Category C; use only if benefits outweigh risks.
Dosing
- Initial dose: 250 mg orally three times daily (t.i.d.) with a meal.
- Maintenance: May titrate to 250 mg BID if well‑tolerated and diarrhea improves.
- Dose adjustment: None required based on weight or gender.
- Missed dose: Take as soon as remembered; do not double dose.
Adverse Effects
| Category | Common (≤10 %) | Serious (≤1 %) |
| GI | Diarrhea, nausea, abdominal pain | Gastrointestinal bleeding, bowel perforation |
| Hepatic | Elevated AST/ALT | Hepatotoxicity, fulminant hepatic failure |
| Other | Fatigue, headache | Allergic reactions, anaphylaxis |
| Metabolic | Hypokalemia | QT prolongation (rare) |
Monitoring
- Baseline: Liver function tests, serum electrolytes, 24‑h urinary 5‑hydroxyindoleacetic acid (5‑HIAA)
- Every 4–6 weeks: AST/ALT, bilirubin, electrolytes
- Every 3 months: 5‑HIAA levels to gauge therapeutic response
- Clinical: Stool frequency, flushing episodes, weight, hydration status
Clinical Pearls
- Synergistic with somatostatin analogues: Telotristat reduces serotonin production while SSAs block receptors; combination offers superior symptom control.
- Food matters: Taking telotristat with a substantial meal maximizes absorption; avoid splitting capsules.
- Monitoring 5‑HIAA is key: A >50 % drop in urinary 5‑HIAA correlates with diarrhea improvement; useful for dose titration.
- Hepatotoxicity vigilance: Even mild elevations in ALT/AST warrant prompt evaluation; discontinue if >3× ULN.
- CYP3A4 interactions: Strong inhibitors (ketoconazole, itraconazole, ritonavir) can increase telotristat levels → ↑ adverse effects; strong inducers (rifampin, carbamazepine) may lower efficacy.
- Pregnancy & lactation: Limited data; consider risk/benefit; monitor maternal liver function.
- Patient education: Emphasize adherence to thrice‑daily dosing; use a pill box to avoid missed doses.
*Telotristat ethyl* offers a targeted pharmacologic approach to managing carcinoid‑syndrome diarrhea and flushing, improving quality of life when SSAs alone are insufficient.