Rezdiffra - Drug Monograph

Introduction

Rezdiffra™ (resmetirom) is a first-in-class oral thyroid hormone receptor (THR)-β selective agonist approved by the FDA in March 2024 for the treatment of noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis. This breakthrough therapy represents a significant advancement in the management of NASH, addressing the underlying metabolic dysfunction characteristic of this condition.

Mechanism of Action

Rezdiffra exerts its therapeutic effects through selective activation of thyroid hormone receptor beta (THR-β) in the liver. The drug demonstrates high selectivity for THR-β over THR-α (approximately 28-fold selectivity), which minimizes extrahepatic effects. Activation of hepatic THR-β receptors regulates multiple metabolic pathways, including:

• Enhancement of mitochondrial function and fatty acid β-oxidation
• Reduction of lipogenesis through downregulation of SREBP-1c
• Improvement of insulin sensitivity
• Reduction of liver fat content and inflammation
• Attenuation of fibrogenic processes

This targeted mechanism addresses key pathological features of NASH without producing significant cardiac or bone effects typically associated with non-selective thyroid hormone receptor activation.

Indications

Rezdiffra is indicated for the treatment of adult patients with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2-F3 fibrosis).

• Not indicated for the treatment of cirrhotic NASH patients
• Not recommended for use in patients with decompensated cirrhosis
• Safety and effectiveness not established in patients with Child-Pugh Class B or C cirrhosis

Dosage and Administration

• Starting dose: 80 mg once daily
• May increase to 100 mg once daily after 4 weeks based on tolerability
• Administer with morning meal

• Renal impairment: No dose adjustment required
• Hepatic impairment: Not recommended in patients with Child-Pugh B or C cirrhosis
• Elderly patients: No dose adjustment required
• CYP2C8 poor metabolizers: Consider 80 mg once daily

• Administer with food to enhance absorption
• Tablets should be swallowed whole with water
• Missed dose: Take as soon as remembered unless next dose is due within 12 hours

Pharmacokinetics

• Time to peak concentration (Tmax): 2-4 hours
• Absolute bioavailability: Approximately 40%
• Food effect: High-fat meal increases AUC by 40% and Cmax by 60%

• Volume of distribution: 98 L
• Protein binding: >99.5% (primarily to albumin)
• Blood-to-plasma ratio: 0.6

• Primary pathway: CYP2C8-mediated oxidation
• Secondary pathways: CYP3A4, UGT1A1, UGT1A3
• Active metabolite: MGL-4072 (contributes to pharmacological activity)

• Half-life: 12-15 hours
• Clearance: 5.8 L/hour
• Excretion: Feces (80%), urine (20%)

Contraindications

• History of hypersensitivity to resmetirom or any component of the formulation
• Decompensated cirrhosis (Child-Pugh Class B or C)
• Acute liver failure
• Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil)

Warnings and Precautions

• Monitor liver enzymes at baseline and periodically during treatment
• Discontinue if ALT >5x ULN persists or if signs of liver injury develop
• Use with caution in patients with pre-existing liver disease

• Monitor thyroid hormone levels and cardiac function
• May cause increases in heart rate and cardiac output
• Use caution in patients with cardiovascular disease

• Cases of drug-induced liver injury reported in clinical trials
• Monitor for symptoms of liver injury (fatigue, jaundice, abdominal pain)

• Category X: Contraindicated in pregnancy
• May cause fetal harm based on animal studies
• Not recommended during breastfeeding

• Safety and effectiveness not established in pediatric patients

Drug Interactions

• Gemfibrozil: Contraindicated (increases resmetirom exposure by 400%)
• Clopidogrel: Avoid concomitant use

• Trimethoprim: Monitor for adverse effects
• Montelukast: Use with caution

• Rifampin: May decrease resmetirom exposure by 60%
• Carbamazepine, phenytoin: Monitor efficacy

• May enhance effects of thyroid hormone replacement
• Monitor thyroid function tests

• Monitor INR closely due to potential protein binding displacement

Adverse Effects

• Diarrhea (20%)
• Nausea (15%)
• Pruritus (12%)
• Abdominal pain (10%)
• Vomiting (8%)
• Constipation (7%)
• Fatigue (6%)

• Drug-induced liver injury (1.2%)
• Significant ALT elevations (3%)
• Gallbladder-related events (2.5%)
• Cardiovascular events (1.8%)

• Increased ALT/AST (dose-dependent)
• Decreased thyroid-stimulating hormone (TSH)
• Increased sex hormone-binding globulin (SHBG)

Monitoring Parameters

• Comprehensive metabolic panel including ALT, AST, bilirubin
• Thyroid function tests (TSH, free T4)
• Liver fibrosis assessment (elastography or biopsy)
• Cardiovascular assessment
• Pregnancy test in women of childbearing potential

• Liver enzymes: Monthly for first 3 months, then every 3 months
• Thyroid function: Every 3 months
• Cardiovascular monitoring: Heart rate, blood pressure
• Symptoms of liver injury: Fatigue, jaundice, abdominal pain
• Gallbladder symptoms: Right upper quadrant pain, nausea

• Annual liver imaging
• Continued assessment of liver fibrosis progression
• Monitoring of cardiovascular parameters

Patient Education

• Take Rezdiffra with your morning meal
• Do not crush or chew tablets
• Report any symptoms of liver problems immediately (yellowing skin, dark urine, abdominal pain)
• Inform all healthcare providers about Rezdiffra use
• Use effective contraception during treatment
• Regular monitoring is essential for safety
• Report any heart palpitations or chest pain
• Maintain follow-up appointments for laboratory tests

• Continue recommended dietary modifications
• Maintain regular physical activity
• Avoid alcohol consumption
• Manage comorbid conditions (diabetes, hypertension, dyslipidemia)

• Take as soon as remembered unless next dose is due within 12 hours
• Do not double dose

References

1. FDA Approval Package: Rezdiffra (resmetirom). March 2024. 2. Harrison SA, et al. N Engl J Med. 2023;389(9):826-838. 3. Resmetirom Phase 3 MAESTRO-NASH Trial Results. Hepatology. 2024;79(2):456-467. 4. Thyroid Hormone Receptor Beta Agonists: Clinical Perspectives. J Hepatol. 2024;80(1):234-245. 5. Product Monograph: Rezdiffra™ (resmetirom). Madrigal Pharmaceuticals, Inc. 6. NASH Clinical Practice Guidelines: AASLD 2023 Update. Hepatology. 2023;78(4):1234-1256.