Resmetirom

Indications

Resmetirom is used for: MASH (Metabolic Dysfunction-Associated Steatohepatitis)with fibrosis, Non Alcoholic Fatty Liver Disease (NASH)

Adult Dose

Metabolic Dysfunction-Associated Steatohepatitis (MASH)/Nonalcoholic Steatohepatitis (NASH) Indicated in conjunction with diet and exercise for treatment of adults with Metabolic Dysfunction-Associated Steatohepatitis (MASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis) Dosage is based on actual body weight Oral <100 kg: 80 mg PO once daily. >100 kg: 100 mg PO once daily. Dosage modification for patients already taking CYP2C8 inhibitor (eg: Statins, Clopidogrel, Montelukast, Gemfibrozil, Clotrimazole) <100 kg, reduce the dosage to 60 mg once daily. >100 kg, reduce the dosage to 80 mg once daily.

Child Dose

Renal Dose

Renal impairment Mild or moderate (CrCl >30 mL/min): No dosage adjustment necessary Severe (CrCl <30 mL/min): Not studied

Administration

Oral Administration Administer with or without food

Contra Indications

Precautions

Hepatotoxicity: Monitor patients during treatment with Resmetirom for elevations in liver tests and for the development of liver-related adverse reactions. Discontinue Resmetirom and continue to monitor the patient if hepatotoxicity is suspected. Gallbladder-Related Adverse Reactions: Cholelithiasis and cholecystitis were observed more often in Resmetirom-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event such as acute cholecystitis is suspected, interrupt Resmetirom treatment until the event is resolved.

Pregnancy-Lactation

Pregnancy There are no available data on resmetirom use in pregnant females to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes There are risks to the mother and fetus related to underlying maternal NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage Animal data Adverse effects on embryofetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recommended dose during organogenesis These effects were likely associated with maternal toxicity, whereas no embryofetal effects were observed at lower dose levels with better tolerance in pregnant rabbits No embryofetal developmental effects occurred in pregnant rats treated with metabolite MGL-3623 A pre- and postnatal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose Lactation There is no information regarding the presence of resmetirom in human or animal milk, effects on the breastfed infant, or effects on milk production

Interactions

Strong or Moderate CYP2C8 Inhibitors: Concomitant use not recommended (strong inhibitor [e.g., gemfibrozil]); or reduce Resmetirom dosage (moderate inhibitor [e.g., clopidogrel]). OATP1B1 and OATP1B3 Inhibitors: Concomitant use with OATP inhibitors (e.g., cyclosporine) is not recommended. Atorvastatin, Pravastatin, Rosuvastatin and Simvastatin: Limit the daily dosage of the statin as recommended. CYP2C8 Substrates: Monitor patients more frequently for substrate-related adverse reactions. Contraindicated (0) Serious (27) asciminib atazanavir belumosudil ceftobiprole medocaril sodium clarithromycin cobicistat cyclosporine darolutamide elvitegravir/cobicistat/emtricitabine/tenofovir DF enasidenib erythromycin base erythromycin ethylsuccinate erythromycin lactobionate erythromycin stearate fostemsavir gemfibrozil glecaprevir/pibrentasvir ledipasvir/sofosbuvir leflunomide lopinavir midostaurin pazopanib rifampin ritonavir rucaparib velpatasvir voxilaprevir

Adverse Effects

Side effects of Resmetirom : >10% Diarrhea (23-33%) Nausea (15-18%) ALT >3x ULN (11-13%) AST >3x ULN (9-12%) 1-10% Pruritus (6-10%) Vomiting (7-8%) Constipation (5-8%) Abdominal pain (5-7%) Dizziness (4%) AST >5x ULN (1-4%) Total bilirubin >2x ULN (1-3%) ALT >5x ULN (2%)

Mechanism of Action

Thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of Metabolic Dysfunction-Associated Steatohepatitis (MASH) in the liver THR-beta action is key to proper liver function, including regulation of mitochondrial activity, such as breakdown of liver fat and control of the level of normal, healthy mitochondria Patients with MASH have reduced levels of THR-beta receptor activity in the liver