Indications
Resmetirom is indicated for use in conjunction with a regimen of diet and exercise for the treatment of adults diagnosed with noncirrhotic nonalcoholic steatohepatitis (NASH), specifically in cases presenting moderate to advanced liver fibrosis, equivalent to stages F2 to F3. However, this medication should not be used in patients with decompensated cirrhosis. It is important to note that this indication has been granted under accelerated approval, premised on the observed improvements in NASH and fibrosis. Continued authorization for this use may rely on further verification and detailed description of clinical benefits in subsequent confirmatory trials.
Pharmacodynamics
Resmetirom acts as a partial agonist of the thyroid hormone receptor-beta (THR-β). In in vitro functional assays, resmetirom demonstrated an 83.8% maximum response when compared to triiodothyronine (T3), with an EC50 of 0.21 µM for THR-β activation. Its efficacy on thyroid hormone receptor-alpha (THR-α) was measured at 48.6% relative to T3, with an EC50 of 3.74 µM. The drug effectively reduces liver fat content and alters the concentrations of free thyroxine (FT4), a known prohormone. Although not definitively proven, some literature suggests that resmetirom may facilitate the conversion of thyroxine (T4) to triiodothyronine (T3). Additionally, resmetirom has been shown to increase the levels of sex hormone-binding globulin.
Absorption
The absorption of resmetirom is characterized by a median Tmax of approximately four hours following multiple daily doses of either 80 mg or 100 mg. When administered with food, there is a noted 33% decrease in Cmax and an 11% decrease in AUC, accompanied by a delay in median Tmax of approximately two hours compared to administration under fasting conditions.
Metabolism
Resmetirom undergoes metabolism primarily through the enzyme CYP2C8. One of its major metabolites, MGL-3623, exhibits a 28-fold lower potency for THR-β compared to the parent compound. At steady state, following administration of 100 mg once daily, MGL-3623 accounts for 33% to 51% of the total resmetirom AUC.
Mechanism of Action
Resmetirom is a selective thyroid hormone receptor-beta (THR-β) agonist designed to address the metabolic dysregulation observed in non-alcoholic fatty liver disease (NAFLD). Thyroid hormones, particularly free thyroxine (FT4) and free triiodothyronine (FT3), are pivotal in regulating lipid metabolism within the liver, primarily through the action of THR-β. Activation of this receptor has been shown to reduce intrahepatic triglycerides, offering a therapeutic approach to this condition. Many individuals with NAFLD also exhibit impaired thyroid function, such as hypothyroidism, which is recognized as a significant risk factor. Hypothyroidism contributes to dysregulated lipolysis in adipose tissue, resulting in increased release of free fatty acids to the liver and facilitating hepatic insulin resistance. Additionally, it may lead to elevated levels of proinflammatory adipokines that exacerbate hepatic inflammation and fibrosis. Resmetirom's mechanism includes promoting lipophagy and enhancing hepatic fatty acid β-oxidation, thereby effectively decreasing liver fat content. Its considerable selectivity, approximately 28 times greater for THR-β over thyroid hormone receptor-alpha (THR-α)-which is predominantly found in the heart and bones-underscores its targeted efficacy in liver-specific pathways.
