Introduction
Vyndaqel (tafamidis) is a first-in-class transthyretin stabilizer indicated for the treatment of transthyretin amyloidosis (ATTR). This rare, progressive disease involves the accumulation of misfolded transthyretin protein as amyloid fibrils in various tissues, leading to organ dysfunction. Vyndaqel represents a targeted therapeutic approach that addresses the underlying pathophysiology of ATTR amyloidosis.
Mechanism of Action
Vyndaqel works through selective stabilization of transthyretin (TTR) tetramers. The drug binds with high affinity and specificity to the thyroxine-binding sites of TTR, preventing the rate-limiting step of tetramer dissociation into monomers. This stabilization inhibits the formation of amyloidogenic monomers that misfold and aggregate into amyloid fibrils. By maintaining the native tetrameric structure of TTR, Vyndaqel reduces amyloid deposition in peripheral nerves, heart, and other tissues.
Indications
Vyndaqel is approved for:
- Treatment of transthyretin-mediated amyloidosis (ATTR) in adults with cardiomyopathy
- Treatment of hereditary transthyretin-mediated amyloidosis (hATTR) in adults with stage 1 symptomatic polyneuropathy
Dosage and Administration
Standard dosing: 61 mg orally once daily (equivalent to 80 mg tafamidis meglumine) Administration: Can be taken with or without food. The capsules should be swallowed whole and not crushed or chewed. Special populations:- Renal impairment: No dosage adjustment required
- Hepatic impairment: Use with caution in moderate hepatic impairment (Child-Pugh B); contraindicated in severe hepatic impairment (Child-Pugh C)
- Elderly: No dosage adjustment required
Pharmacokinetics
Absorption: Tafamidis is rapidly absorbed with median Tmax of approximately 1.5 hours. Food does not significantly affect absorption. Distribution: Highly bound to plasma proteins (>99%), primarily albumin. Steady-state volume of distribution is approximately 16 L. Metabolism: Primarily undergoes glucuronidation via UGT1A1, UGT1A3, and UGT1A9. No significant cytochrome P450 metabolism. Elimination: Primarily excreted in feces (59%) with minimal renal excretion (<0.5%). Terminal elimination half-life is approximately 49 hours.Contraindications
- Hypersensitivity to tafamidis or any component of the formulation
- Severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Hepatic impairment: Use with caution in patients with moderate hepatic impairment. Monitor liver function tests regularly. Vitamin A deficiency: Tafamidis may alter vitamin A levels. Consider supplementation if deficiency occurs. Pregnancy: Use only if potential benefit justifies potential risk to fetus (Category C) Lactation: Decision should be made to discontinue nursing or discontinue drug Monitoring: Regular assessment of liver function, nutritional status, and clinical response is recommendedDrug Interactions
Strong UGT inducers: Drugs such as rifampin may decrease tafamidis exposure Vitamin A: May alter vitamin A metabolism and transport Other TTR binders: Potential interaction with other drugs that bind TTR (e.g., NSAIDs, some thyroid hormones)Adverse Effects
Most common adverse reactions (≥5%):- Urinary tract infection
- Diarrhea
- Upper abdominal pain
- Increased blood creatinine
- Female genital tract infection
- Worsening of congestive heart failure
- Atrioventricular block
- Atrial fibrillation
- Cardiac failure
Monitoring Parameters
- Liver function tests (baseline and periodically)
- Renal function (serum creatinine)
- Nutritional status (including vitamin A levels)
- Cardiac function (echocardiogram, ECG)
- Neurological assessment (for polyneuropathy patients)
- Clinical symptoms of disease progression
Patient Education
- Take Vyndaqel exactly as prescribed, once daily
- Do not stop taking without consulting your healthcare provider
- Report any new or worsening symptoms, particularly related to heart function
- Inform all healthcare providers about Vyndaqel use
- Be aware of potential vitamin A deficiency symptoms (night blindness, dry eyes)
- Keep regular follow-up appointments for monitoring
- Store at room temperature (20-25°C)
References
1. FDA Prescribing Information: Vyndaqel (tafamidis) 2. Maurer MS, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016 3. Coelho T, et al. Tafamidis for transthyretin familial amyloid polyneuropathy. Neurology. 2012;79(8):785-792 4. Bulawa CE, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci USA. 2012;109(24):9629-9634 5. Planté-Bordeneuve V, et al. Long-term treatment with tafamidis for patients with transthyretin familial amyloid polyneuropathy. J Neurol. 2021;268(1):274-285