Dr. Ahmed The FDA Approved Rezdiffra (Resmetirom) for the treatment of non-cirrhotic, non-alcoholic steatohepatitis, also called MASH (Metabolic-dysfunction Associated SteatoHepatitis).
The drug is indicated for moderate to advanced liver fibrosis consistent with Stage F2 and Stage F3 Fibrosis.
The drug is not intended for patients who have decompensated cirrhosis.
What is Resmetirom and How Does it Work?
Resmetirom is an agonist of THR-β (Thyroid hormone receptor-Beta). Unlike Levothyroxin which acts on both THR-α and THR-β receptors, Resmetiron preferentially activates THR-β.
Receptors of THR-β are primarily present in the liver while THR-α (thyroid hormone receptors-alpha) is present outside the liver including the heart and bones.
The concept of intra-hepatic hypothyroidism was delineated in patients presenting with metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic fatty liver disease (NAFLD), encompassing both fatty liver disease (FLD) and non-alcoholic steatohepatitis (NASH), wherein intrahepatic lipotoxicity was evident.
Similar observations were made in subjects afflicted with hypothyroidism. Furthermore, the administration of thyroid hormone supplementation exhibited favorable outcomes by mitigating the consequences of lipotoxicity.
The activation of THR-β receptors promotes lipid clearance, generates new mitochondria, and stimulates Beta-acid oxidation of fatty acids [Ref]. In addition, it causes the uptake of LDL from the blood reducing atherosclerosis.
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Rezdiffra (Resmetirom) Dosage Forms:
The drug is available in 3 different strengths:
- 60 mg
- 80 mg, and
- 100 mg
The tablets are oval-shaped, film-coated tablets, marked as P60, P80, and P100 on one side.
Rezdiffra (Resmetirom) Dosing Guidelines:
The recommended daily doses are based on actual body weight [Ref].
For patients weighing less than 100 kg, the recommended daily dose is 80 mg per day.
For patients weighing 100 kg or more, the recommended daily dose is 100 mg per day.
The drug is not recommended with concomitant strong CYP2C8 Inhibitors such as Gemfibrozil.
With moderate CYP2C8 Inhibitor like Clopidogrel, the dosing guidelines recommended are:
- <100 kg: 60 mg per day
- 100 kg or more: 80 mg per day.
Rezdiffra (Resmetirom) tablets may be administered with or without food.
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Warnings and Contraindications:
The manufacturer has not mentioned any contraindications to its use, except for avoiding it with strong CYP2C8 Inhibitors.
Some of the serious warnings include:
Hepatotoxicity:
Liver dysfunction has been reported in clinical trials with the use of Rezdiffra (Resmetirom).
Patients who developed drug-induced liver dysfunction had raised ALT, AST, and Bilirubin without significant elevations in alkaline phosphatase.
In addition, IgG levels were also elevated suggesting drug-induced liver disease (drug-induced autoimmune like hepatitis). Discontinuation of the drug resulted in improvement in the liver enzymes.
The manufacturer recommends monitoring for hepatotoxicity. Clinical features of hepatotoxicity include nausea, right upper quadrant pain, jaundice, fever, rash, and eosinophilia.
Re-introducing the drug after the liver enzymes return to baseline is a decision of the treating physician, weighing the risks and benefits.
For patients with persistently raised liver enzymes after discontinuing the drug, other causes should be investigated.
Gallbladder-related side effects:
Gallstones, cholecystitis, and gallstones-associated pancreatitis were reported in clinical trials.
In acute settings, the drug should be discontinued until the acute gallbladder-related disease is cured.
Drug interactions with statins:
Adverse events associated with statins such as myopathy, elevated liver enzymes, and rhabdomyolysis are more likely with concomitant Rezdiffra (Resmetirom) treatment.
Patients on Simvastatin, atorvastatin, rosuvastatin, and pravastatin were observed to have increased drug exposure with concomitant Rezdiffra (Resmetirom) therapy.
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Specific Population:
Rezdiffra (Resmetirom) should be avoided in children, pregnant women, breastfeeding women, and patients with advanced kidney impairment.
In this patient population, the drug has not been studied.
In those with liver disease, dosage adjustment is not required in patients with mild liver disease (Child Class A Cirrhosis).
In moderate (Child Class B) and Severe (Child Class C) liver cirrhosis, there is an increase in drug exposure, hence treatment with Rezdiffra (Resmetirom) is not recommended.
Rezdiffra (Resmetirom) Mechanism of Action (MOA):
Rezdiffra (Resmetirom) is a partial thyroid hormone receptor agonist primarily acting on THR-β receptors.
In an in vitro functional assay:
Resmetirom showed 83.8% efficacy compared to triiodothyronine (T3) for THR-β activation and 48.6% efficacy relative to T3 for THR-α agonism.
Parameter | Resmetirom (THR-β) | Resmetirom (THR-α) |
| Maximum Response | 83.8% | 48.6% |
| EC50 (µM) | 0.21 | 3.74 |
Resmetirom reduces liver fat content and reduces prohormone FT4 and FT4 levels.
Half-life: 4.5 hours
Peak drug levels after administration: 4 hours
Protein-binding: 99%
Metabolism: Via CYP2C8
Excretion: 67% feces, 24% urine
Resmetirom Potential Drug Interactions:
Drug Interaction | Effect on Resmetirom Pharmacokinetics |
| Clopidogrel | Cmax increased 1.3-fold; AUC increased 1.7-fold |
| Pioglitazone | Cmax unchanged; AUC increased 1.5-fold |
| Simvastatin | Cmax increased 1.4-fold; AUC increased 1.7-fold |
| Rosuvastatin | Cmax increased 2.9-fold; AUC increased 1.8-fold |
| Pravastatin | Cmax increased 1.3-fold; AUC increased 1.4-fold |
| Atorvastatin | Cmax unchanged; AUC increased 1.4-fold |
| Atorvastatin lactone | Cmax increased 2.0-fold; AUC increased 1.8-fold |
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