Resmetirom

Identification

Summary

Resmetirom is a thyroid hormone receptor-beta agonist used to treat noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis in adults.

Brand Names
Rezdiffra
Generic Name
Resmetirom
DrugBank Accession Number
DB12914
Background

Resmetirom is a thyroid hormone receptor-beta (THR-beta) agonist. On March 14, 2024, it was approved by the FDA as the first treatment of liver fibrosis due to noncirrhotic non-alcoholic steatohepatitis (NASH), which is a form of non-alcoholic fatty liver disease (NAFLD).6

Thyroid hormones directly regulate lipid metabolism in the liver; thus, impaired thyroid function, such as low serum thyroid hormone levels, is often observed in NAFLD.3 Resmetirom works to reduce liver fat by stimulating fatty acid degradation and oxidation.6

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 435.22
Monoisotopic: 434.0297083
Chemical Formula
C17H12Cl2N6O4
Synonyms
  • 1,2,4-Triazine-6-carbonitrile, 2-[3,5-dichloro-4-[[1,6-dihydro-5-(1-methylethyl)-6-oxo-3-pyridazinyl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-
  • 2-[3,5-Dichloro-4-[[1,6-dihydro-5-(1-methylethyl)-6-oxo-3-pyridazinyl]oxy]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile
  • Resmetirom
External IDs
  • MGL 3196
  • MGL-3196
  • MGL3196
  • VIA-3196

Pharmacology

Indication

Resmetirom is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). Its use should be avoided in patients with decompensated cirrhosis.5

This indication is approved under accelerated approval based on the improvement of NASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Adjunct therapy in treatment ofAdvanced liver fibrosis•••••••••••••••••••••••
Adjunct therapy in treatment ofModerate liver fibrosis•••••••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Resmetirom is a partial agonist of the thyroid hormone receptor-beta (THR-β). Resmetirom produced 83.8% of the maximum response compared to triiodothyronine (T3), with an EC50 of 0.21 µM in an in vitro functional assay for THR-β activation. The same functional assay for thyroid hormone receptor-alpha (THR-α) agonism showed 48.6% efficacy for resmetirom relative to T3, with an EC50 of 3.74 µM.5

Resmetirom decreases liver fat content and the concentrations of free thyroxine (FT4), which is a prohormone.5 Although it is inconclusive, there have been some reports in the literature suggesting that resmetirom may convert thyroxine (T4) to triiodothyronine (T3).3 It increases the concentrations of sex hormone-binding globulin.5

Mechanism of action

Thyroid hormones, such as FT4 and free triiodothyronine (FT3), are key regulators of lipid metabolism in the liver.1 Thyroid hormone receptor-beta (THR-β) is the major form of the thyroid hormone receptor in the liver,2 and stimulation of this receptor reduces intrahepatic triglycerides.5

Many patients with non-alcoholic fatty liver disease (NAFLD) present with impaired thyroid function, such as hypothyroidism, rendering it a significant risk factor for NAFLD.1,2,3 Hypothyroidism has also been linked to dysregulated adipose tissue lipolysis and increased free fatty acid release from the adipose to the liver, promoting hepatic insulin resistance.1 Increased circulating levels of proinflammatory adipokines, which contribute to hepatic inflammation and fibrosis, may also be observed.1

Resmetirom is a partial agonist of THR-β 5 that promotes lipophagy and hepatic fatty acid β-oxidation, thereby reducing liver fat.3 It is approximately 28 times more selective than FT3 for THR-β versus thyroid hormone receptor-alpha (THR-α), which is mainly expressed in the heart and bones.4

TargetActionsOrganism
AThyroid hormone receptor beta
partial agonist
Humans
Absorption

The median Tmax is approximately four hours following multiple daily doses of resmetirom 80 mg or 100 mg.5

Concomitant food administration resulted in a 33% decrease in Cmax, an 11% decrease in AUC, and a delay in median Tmax by about two hours compared to an under-fasted condition.5

Volume of distribution

Resmetirom apparent volume of distribution (Vd/F) at steady-state is 68 (227%) L.5

Protein binding

Resmetirom is greater than 99% protein-bound.5

Metabolism

Resmetirom is metabolized by CYP2C8. MGL-3623 is a major metabolite with a 28-times lower potency for THR-β than resmetirom. MGL-3623 represents 33% to 51% of resmetirom AUC at steady-state following administration of 100 mg once daily.5

Route of elimination

Following oral administration of a 100 mg radio-labeled dose of resmetirom, approximately 67% of the total radioactive dose was recovered in the feces, mostly as metabolites and 24% of the total radioactive dose was recovered in the urine. Unchanged labeled resmetirom was not detected in feces and accounted for 1% of the dose recovered in urine. A metabolite MGL-3623 accounted for 3.3% and 16% of the dose recovered in feces and urine, respectively. Oxalic acid metabolite was observed in plasma but not in urine.5

Half-life

The median terminal plasma half-life is 4.5 hours.5

Clearance

The steady state apparent clearance (CL/F) is 17.5 (56.3%) L/h.5

Adverse Effects
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Toxicity

There is no information regarding the acute toxicity and overdosage of resmetirom.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Resmetirom can be increased when combined with Abatacept.
AbirateroneThe metabolism of Resmetirom can be decreased when combined with Abiraterone.
AcetylcysteineThe serum concentration of Resmetirom can be increased when it is combined with Acetylcysteine.
AdalimumabThe metabolism of Resmetirom can be increased when combined with Adalimumab.
AlmotriptanThe metabolism of Almotriptan can be decreased when combined with Resmetirom.
Food Interactions
  • Take with or without food. A high fat meal may reduce Cmax and AUC delay Tmax, but not to a clinically significant extent.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
RezdiffraTablet, coated80 mg/1OralMadrigal Pharmaceuticals, Inc.2024-03-14Not applicableUS flag
RezdiffraTablet, coated60 mg/1OralMadrigal Pharmaceuticals, Inc.2024-03-14Not applicableUS flag
RezdiffraTablet, coated100 mg/1OralMadrigal Pharmaceuticals, Inc.2024-03-14Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diarylethers. These are organic compounds containing the dialkyl ether functional group, with the formula ROR', where R and R' are aryl groups.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Ethers
Direct Parent
Diarylethers
Alternative Parents
Phenoxy compounds / Phenol ethers / Dichlorobenzenes / Pyridazinones / Aryl chlorides / 1,2,4-triazines / Heteroaromatic compounds / Lactams / Nitriles / Azacyclic compounds
show 3 more
Substituents
1,2,4-triazine / 1,3-dichlorobenzene / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Benzenoid / Carbonitrile / Chlorobenzene / Cyanide
show 18 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
RE0V0T1ES0
CAS number
920509-32-6
InChI Key
FDBYIYFVSAHJLY-UHFFFAOYSA-N
InChI
InChI=1S/C17H12Cl2N6O4/c1-7(2)9-5-13(22-23-15(9)26)29-14-10(18)3-8(4-11(14)19)25-17(28)21-16(27)12(6-20)24-25/h3-5,7H,1-2H3,(H,23,26)(H,21,27,28)
IUPAC Name
2-(3,5-dichloro-4-{[6-oxo-5-(propan-2-yl)-1,6-dihydropyridazin-3-yl]oxy}phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile
SMILES
CC(C)C1=CC(OC2=C(Cl)C=C(C=C2Cl)N2N=C(C#N)C(=O)NC2=O)=NNC1=O

References

General References
  1. Hatziagelaki E, Paschou SA, Schon M, Psaltopoulou T, Roden M: NAFLD and thyroid function: pathophysiological and therapeutic considerations. Trends Endocrinol Metab. 2022 Nov;33(11):755-768. doi: 10.1016/j.tem.2022.08.001. Epub 2022 Sep 26. [Article]
  2. Li L, Song Y, Shi Y, Sun L: Thyroid Hormone Receptor-beta Agonists in NAFLD Therapy: Possibilities and Challenges. J Clin Endocrinol Metab. 2023 Jun 16;108(7):1602-1613. doi: 10.1210/clinem/dgad072. [Article]
  3. Karim G, Bansal MB: Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, beta-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60. Epub 2023 May 1. [Article]
  4. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11. [Article]
  5. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
  6. FDA: FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease [Link]
PubChem Compound
15981237
PubChem Substance
347829063
ChemSpider
13112637
BindingDB
50012905
RxNav
2677894
ChEMBL
CHEMBL3261331
ZINC
ZINC000034842512
Wikipedia
Resmetirom

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral100 mg/1
Tablet, coatedOral60 mg/1
Tablet, coatedOral80 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11564926No2013-09-172033-09-17US flag
US10376517No2013-09-172033-09-17US flag
US9266861No2013-09-172033-09-17US flag
US7452882No2006-09-122026-09-12US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0126 mg/mLALOGPS
logP3.6ALOGPS
logP2.97Chemaxon
logS-4.5ALOGPS
pKa (Strongest Acidic)5.65Chemaxon
pKa (Strongest Basic)-5.2Chemaxon
Physiological Charge-1Chemaxon
Hydrogen Acceptor Count6Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area136.25 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity102.45 m3·mol-1Chemaxon
Polarizability39.4 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0000900000-d61c515b84b6556167eb
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-2003900000-41867e62596ccd4396cd
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0003900000-5f0547cade512726d8a7
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-02uc-5009800000-7e261824a21b5c1546ce
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-5119300000-56cb83c41baf56a05ccc
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000000000-1a4cf3d5a21e199cc2a1
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-187.56334
predicted
DeepCCS 1.0 (2019)
[M+H]+189.92134
predicted
DeepCCS 1.0 (2019)
[M+Na]+197.58514
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Partial agonist
General Function
Zinc ion binding
Specific Function
Nuclear hormone receptor that can act as a repressor or activator of transcription. High affinity receptor for thyroid hormones, including triiodothyronine and thyroxine.
Gene Name
THRB
Uniprot ID
P10828
Uniprot Name
Thyroid hormone receptor beta
Molecular Weight
52787.16 Da
References
  1. Karim G, Bansal MB: Resmetirom: An Orally Administered, Smallmolecule, Liver-directed, beta-selective THR Agonist for the Treatment of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis. touchREV Endocrinol. 2023 May;19(1):60-70. doi: 10.17925/EE.2023.19.1.60. Epub 2023 May 1. [Article]
  2. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11. [Article]
  3. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Protein homodimerization activity
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX-alpha to form both the...
Gene Name
UGT1A4
Uniprot ID
P22310
Uniprot Name
UDP-glucuronosyltransferase 1-4
Molecular Weight
60024.535 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Retinoic acid binding
Specific Function
UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform has specificity for phenols. Isoform 2 lacks trans...
Gene Name
UGT1A9
Uniprot ID
O60656
Uniprot Name
UDP-glucuronosyltransferase 1-9
Molecular Weight
59940.495 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenad...
Gene Name
SLC22A8
Uniprot ID
Q8TCC7
Uniprot Name
Solute carrier family 22 member 8
Molecular Weight
59855.585 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Transporter activity
Specific Function
Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes.
Gene Name
ABCB11
Uniprot ID
O95342
Uniprot Name
Bile salt export pump
Molecular Weight
146405.83 Da
References
  1. FDA Approved Drug Products: REZDIFFRA (resmetirom) tablets, for oral use [Link]

Drug created at October 21, 2016 01:15 / Updated at April 03, 2024 01:15