PubChem compound: 15981237
Resmetirom is a liver-directed partial agonist for 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. THR-β is the predominant form of THR in the liver. Stimulation of THR-β in the liver improves mitochondrial function and lipid metabolism, and increases fatty acid β-oxidation, thereby reducing lipotoxic liver fat, inflammation and liver fibrosis. Resmetirom's liver directed THR-β agonism is particularly relevant in the treatment of MASH and leads to minimal off-target activity on THR-α in tissues such as heart and bone.
Resmetirom decreases liver fat content as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) or FibroScan controlled attenuation parameter (CAP). Reductions in liver fat content by MRI-PDFF were observed at 16 (the first assessment) and 52 weeks of treatment. Reductions in liver fat content by CAP were observed at 52 weeks of treatment.
Resmetirom reduces blood low density lipoprotein (LDL) cholesterol, apolipoprotein B, lipoprotein (a) and triglyceride levels. Reductions in all lipid endpoints were observed initially after 4 weeks (the first assessment) and sustained at 24 and through 52 weeks of treatment.
Decreased concentrations of prohormone FT4 were observed at the first assessment at 4 weeks of treatment. Similar decreases in FT4 were observed during treatment.
Resmetirom increased concentrations of sex hormone binding globulin (SHBG) at the first assessment at 4 weeks of treatment and at longer durations of treatment; by week 52, SHBG increased from baseline 145% (95% CI: 128, 160%) for 80 mg, 205% (95% CI: 182, 229%) for 100 mg and -0.4% (95% CI: -4, 2%) for placebo. No known adverse reactions were associated with SHBG elevations.
At a dose of 200 mg given for 7 days, resmetirom did not prolong the QT interval, PR interval, QRS interval, or alter heart rate in a study in healthy subjects.
Following once daily doses, steady state is typically reached within 3 to 6 days of dosing. Resmetirom steady state exposure increases in a dose proportional manner between doses of 40 mg (0.5 times the lowest approved recommended dose) and 100 mg. Resmetirom exposure increases in a greater than dose-proportional manner between doses of 100 mg and 200 mg (2 times the highest approved recommended dose) by about 5.6-fold. Resmetirom exposure increased 1.5- to 3-fold following once daily dosing; however, the MGL-3623 metabolite does not accumulate. The estimated resmetirom systemic exposure at steady state in MASH patients derived from population pharmacokinetic (PK) modeling is summarised in the table below. Resmetirom exposure is similar between MASH patients with F2 stage fibrosis and F3 stage fibrosis.
Resmetirom estimated systemic exposure at steady state in patients with MASH with fibrosis (F2 and F3):
| Resmetirom 80 mg Mean (CV%) | Resmetirom 100 mg Mean (CV%) | |
|---|---|---|
| Cmax,ss (ng/mL) | 773 (45.4) | 953 (46.1) |
| AUCtau,ss (ng*h/mL) | 5780 (66.1) | 7740 (71.8) |
The resmetirom median time to maximum plasma concentration (Tmax) is approximately 4 hours following multiple daily doses of resmetirom 80 mg or 100 mg.
Concomitant administration with a high-fat meal (approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) had no clinically relevant effect on the oral bioavailability of resmetirom. Concomitant food administration resulted in a 33% decrease in Cmax, an 11% decrease in AUC, and a delay in median Tmax by about 2 hours compared to under fasted condition.
The apparent volume of distribution at steady-state (Vd/F) of resmetirom is highly correlated with body weight. Based on population PK analysis, in MASH patients with fibrosis stage F2/F3 and a median body weight of 99 kg, the median Vd/F at steady state was 62.8 L. Resmetirom is over 99% protein-bound in plasma.
In vitro studies showed that resmetirom is partially metabolised by CYP2C8 and is a substrate of transporters including OATP1B1, OATP1B3 and BCRP.
Resmetirom has two major metabolites: oxalic acid and MGL-3623. MGL-3623 is approximately 30-fold less potent at THR-β than resmetirom. MGL-3623 represented approximately 16% and oxalic acid represented approximately 15% of total plasma AUC in a repeat-dose oral mass balance study using a 100 mg solution dose of resmetirom. MGL-3623 does not accumulate with repeated dosing of resmetirom.
Based on population pharmacokinetic analysis, in MASH patient with fibrosis stage F2/F3, the median terminal plasma half-life (t½) of resmetirom 4.5 hours. The mean apparent clearance (CL/F) at steady state is 18.6 (64.4%) L/h.
The use of resmetirom should be avoided in patients with decompensated cirrhosis. Moderate or severe hepatic impairment (Child-Pugh B or C) increases resmetirom Cmax and AUC, which may increase the risk of adverse reactions.
The disposition of resmetirom and its metabolite were compared in non-MASH patients with hepatic impairment (mild [N=10], moderate [N=10], and severe [N=3] as indicated by the Child-Pugh method) and subjects with normal hepatic function (n=8) following repeated 80 mg dosing of resmetirom for 6 days.
Compared to subjects with normal hepatic function, following repeated 80 mg dosing for 6 days, the percent ratio of geometric mean of AUC for resmetirom, were 115%, 303%, and 2,350% in patients with mild, moderate, and severe hepatic impairment, respectively. The percent ratio of geometric means for Cmax were 133%, 196%, and 919%, respectively.
The disposition of resmetirom and its metabolite were compared in MASH patients, with MASH cirrhosis categorised with mild hepatic impairment (Child-Pugh Class A) and non-cirrhotic MASH following repeated 100 mg dosing of resmetirom for 6 days. The PK disposition of resmetitom was not altered in MASH cirrhosis patients with mild hepatic impairment (Child-Pugh Class A) compared with non-cirrhotic MASH patients. No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A cirrhosis).
The safety and effectiveness of resmetirom have not been established in patients with MASH cirrhosis.
The pharmacokinetics of resmetirom and its metabolite MGL-3623 were evaluated in subjects with mild, moderate and severe renal impairment. Renal excretion is a minor elimination pathway. In patients with mild and moderate renal impairment, exposure to resmetirom was comparable to that in subjects with normal renal function and was not clinically relevant. In patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), repeated dosing resulted in an approximately 1.5-fold increase in AUC and a 1.3-fold increase in Cmax for resmetirom compared to matched healthy controls. Exposure to the metabolite MGL-3623 was increased to a lesser extent. These increases remained within the variability observed in the general population at the recommended dose. Importantly, the observed changes in exposure were not associated with clinically meaningful alterations in pharmacodynamic markers (including thyroid hormones, lipids, and SHBG) or safety signals. Therefore, no dose adjustment is considered necessary in patients with renal impairment.
The PK of resmetirom were not affected by age (<65 years and ≥65 years), gender or race. Effects of ethnicity were not evaluated.
The results from the population PK model suggest a faster clearance of resmetirom in patients with higher body weight. No parameter was identified other than body weight in the exposure-response model of resmetirom that impacted efficacy parameters.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In a 2-year study in CD-1 mice, resmetirom produced leiomyoma or leiomyosarcoma in the uterus at a dose of 100 mg/kg/day (51 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in female mice at doses of up to 30 mg/kg/day (14 times the maximum recommended dose based on AUC) or in male mice at doses of up to 100 mg/kg/day (35 times the maximum recommended dose based on AUC).
In a 2-year study in Sprague-Dawley rats, resmetirom produced benign fibroadenoma in the mammary gland of males at a dose of 30 mg/kg/day (6.5 times the maximum recommended dose based on AUC). No tumorigenic effects were observed in male rats at doses of up to 6 mg/kg/day (3.7 times the maximum recommended dose based on AUC) or in female rats at doses of up to 30 mg/kg/day (3.4 times the maximum recommended dose based on AUC).
In a fertility and early embryonic development study in male and female rats, there were no adverse effects of resmetirom on male or female fertility, reproductive organs, reproductive function or early embryonic development at oral doses up to 30 mg/kg/day (6.9 and 2.6 times the maximum recommended dose based on AUC, for males and females respectively).
No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.