What baseline tests and ongoing monitoring are required when starting a patient on resmetirom?

Monitoring Requirements for Resmetirom

Check liver enzymes at 12 weeks after starting resmetirom to assess for hepatotoxicity, and educate patients immediately about gastrointestinal symptoms and signs of liver injury that may occur early in treatment. 1

Baseline Assessment Before Starting

Before initiating resmetirom, ensure you have:

• Baseline liver enzymes (ALT, AST) to establish a reference point for monitoring 1
• Confirmation of non-cirrhotic status and exclusion of decompensated cirrhosis 2
• Review of concomitant medications, particularly statins and CYP2C8 inhibitors 1, 2
• Baseline lipid panel if monitoring cardiovascular risk 1

Critical Early Monitoring (First 12 Weeks)

Liver Enzyme Monitoring

Do not check liver enzymes before 12 weeks unless the patient develops symptoms of hepatotoxicity. 1 This is crucial because:

• Transient ALT/AST elevations occur early (first 4 weeks), particularly in patients on statins, with mean increases <1.5x baseline 1
• These elevations typically resolve by 8 weeks without treatment discontinuation 1
• Checking enzymes too early may lead to unnecessary discontinuation and misinterpretation of normal drug effects 1

Patient Education on Symptoms

Immediately educate patients to report symptoms of hepatotoxicity: 1

• Fatigue, nausea, vomiting
• Right upper quadrant pain or tenderness
• Jaundice, fever, rash
• Eosinophilia (>5%)

Also warn about common gastrointestinal side effects: 1

• Diarrhea (median onset 6-17 days, duration ~20 days)
• Nausea (median onset 5-28 days, duration ~26-28 days)
• Constipation, abdominal pain, vomiting

These GI symptoms are dose-dependent and led to discontinuation in 8 per 100 person-years in the 100 mg group. 1 Real-world data shows 16% discontinuation rate, primarily due to adverse events. 3

Structured Monitoring Schedule

At 12 Weeks (Safety Assessment)

Check liver enzymes (ALT, AST, total bilirubin, alkaline phosphatase) 1, 2

• This is the first mandatory laboratory checkpoint for hepatotoxicity assessment 1
• If persistent and significant elevation occurs, carefully consider discontinuation 1
• One case of drug-induced autoimmune-like hepatitis occurred with peak ALT 58x ULN, AST 66x ULN, and TB 15x ULN 2

At 6 Months (Disease Monitoring)

Consider checking: 1

• Aminotransferases for disease monitoring
• VCTE (vibration-controlled transient elastography) or PDFF (proton density fat fraction) may suggest early response
• Important caveat: Absence of response at 6 months is inadequate to fully assess treatment response 1

At 12 Months and Annually (Efficacy Monitoring)

Continue treatment if: 1

• Aminotransferases improved (compared to baseline or normalization)
• Aminotransferases stable but other disease improvement present (e.g., MRI-PDFF improvement)
• MRI-PDFF reduction of 30% suggests likely histologic response 1
• Liver stiffness measurement (LSM) should be part of regular monitoring every 12 months by transient elastography or MRE 1

Discontinue treatment if: 1

• No response in MRI-PDFF if obtained at baseline

• 30% increase in liver stiffness or worsening

• Drug not tolerated

Drug Interaction Monitoring

Statin Dose Adjustments Required

If patient is on statins, adjust doses as follows: 1, 2

• Rosuvastatin and simvastatin: limit to 20 mg/day
• Pravastatin and atorvastatin: limit to 40 mg/day
• Monitor for statin-related adverse reactions: elevation of liver tests, myopathy, rhabdomyolysis 2

This is FDA-mandated despite resmetirom reducing LDL-C by 14-20%, which offsets the statin dose reduction. 1

CYP2C8 Inhibitor Considerations

• Avoid strong CYP2C8 inhibitors (gemfibrozil) 1, 2
• With moderate CYP2C8 inhibitors (clopidogrel), reduce resmetirom dose and monitor more closely 1, 2
• Avoid OATP1B1/1B3 inhibitors (cyclosporine) 1

Thyroid Monitoring

Thyroid monitoring is generally not required. 1 Despite resmetirom reducing free T4 by 16-19% at 52 weeks:

• No increase in endocrine adverse events occurred 1
• TSH and T3/free T3 remained within normal limits 1
• The mechanism is hepatic upregulation of DIO1 (type 1 deiodinase), not central hypothalamic-pituitary-thyroid axis suppression 1
• Resmetirom does not interfere with thyroid hormone replacement therapy 1

Gallbladder Monitoring

Maintain clinical vigilance for gallbladder-related events: 2

• Cholelithiasis, acute cholecystitis, and obstructive pancreatitis occurred more frequently with resmetirom 2
• If suspected, obtain gallbladder diagnostic studies 2
• Interrupt treatment until acute gallbladder event resolves 2

Common Pitfalls to Avoid

1. Do not discontinue treatment before 12 weeks based solely on transient liver enzyme elevations, as these are expected and typically resolve 1
2. Do not assess efficacy at 3 months - changes in NITs at 3 months were not reliably predictive of treatment response 1
3. Do not rely on VCTE alone for treatment response - histologic improvements may occur without corresponding VCTE or liver enzyme changes 1
4. Do not forget to adjust statin doses - this is an FDA requirement despite the favorable lipid effects of resmetirom 1, 2