Thyroid Hormone Receptor-β Agonists Drug-Drug Interaction Table

What Is the Thyroid Hormone Receptor-β Agonist Drug Class?

THR-β agonists selectively activate the beta isoform of the thyroid hormone receptor, which predominates in the liver and mediates the lipid-lowering and metabolic effects of thyroid hormone without the cardiac, bone, and muscle toxicities driven by the alpha isoform. Resmetirom is the only FDA-approved agent in the class as of early 2025. The FDA granted approval on 14 March 2024 under the brand name Rezdiffra for adults with noncirrhotic MASH and liver fibrosis stages F2 or F3. 1

Mechanism of Action

Resmetirom binds THR-β with approximately 28-fold selectivity over THR-α. 2 By activating hepatic THR-β, it increases mitochondrial fatty acid oxidation, reduces de novo lipogenesis, and accelerates LDL-receptor-mediated clearance. These effects converge on the histological endpoints relevant to MASH: fibrosis regression and MASH resolution.

Key Trial: MAESTRO-NASH

The MAESTRO-NASH trial (N=966) showed that resmetirom 100 mg achieved MASH resolution without fibrosis worsening in 25.9% of patients versus 14.2% placebo (P<0.001) at 52 weeks, and fibrosis improvement of at least one stage in 29.9% versus 19.9% placebo (P<0.001). 3 LDL-C fell by 16.3% with the 100 mg dose at week 52 versus a 0.2% increase in the placebo group.

Isoform Selectivity and Safety Profile

Because THR-α drives cardiac chronotropy and bone resorption, beta-selective agonism at therapeutic doses does not increase heart rate or suppress TSH to clinically meaningful levels in most patients. 4 The prescribing information notes that in MAESTRO-NASH, mean TSH remained within normal limits across both dose groups at all time points. 1

Pharmacokinetic Profile Driving DDI Risk

Understanding where resmetirom sits in the metabolic and transport network is the foundation for every interaction listed below.

CYP Metabolism

Resmetirom is primarily metabolized by CYP2C8, with minor contributions from CYP3A4 and CYP2C19. 1 It is a moderate inhibitor of CYP2C8, meaning it can increase the AUC of sensitive CYP2C8 substrates by 2- to 5-fold. 5 Clinicians should recall that the FDA defines a moderate CYP inhibitor as one that increases a sensitive substrate AUC by a factor of 2 to 5. 6

Transporter Interactions

Resmetirom is a substrate and inhibitor of the hepatic uptake transporters OATP1B1 and OATP1B3. 1 These transporters move many statins and other drugs into hepatocytes for first-pass extraction. Inhibition of OATP1B1 by resmetirom raises plasma concentrations of co-administered statin substrates, increasing myopathy risk. 7 The clinical pharmacology review underlying the FDA label used a physiologically based pharmacokinetic (PBPK) model to quantify these effects, projecting rosuvastatin AUC increases of approximately 2.0-fold.

P-glycoprotein

Resmetirom is also a P-glycoprotein (P-gp) inhibitor in vitro. 1 The clinical relevance of this finding appears modest for most co-prescribed drugs, but digoxin concentrations may rise and warrant monitoring. 8

Effect of Strong CYP2C8 or OATP Inhibitors on Resmetirom

Because resmetirom is itself a CYP2C8 substrate, strong inhibitors of CYP2C8 (gemfibrozil) can increase resmetirom exposure substantially. The prescribing information recommends avoiding concurrent gemfibrozil. 1 Cyclosporine, a potent OATP inhibitor, is contraindicated with resmetirom because modeled interactions predict a greater-than-4-fold increase in resmetirom AUC. 1

Complete DDI Table: Resmetirom and Co-Prescribed Agents

The table below covers every interaction described in the current FDA label plus interactions inferred from published OATP1B1/CYP2C8 pharmacokinetic data. Severity ratings follow the standard clinical pharmacology convention: Contraindicated, Avoid, Dose Cap/Adjust, or Monitor.

| Interacting Drug | Mechanism | Expected Effect on Perpetrator or Victim | Severity | Clinical Action | |---|---|---|---|---| | Cyclosporine | Strong OATP1B1/1B3 inhibitor | Resmetirom AUC increases >4-fold | Contraindicated | Do not co-prescribe | | Gemfibrozil | Strong CYP2C8 inhibitor | Resmetirom AUC increases significantly | Avoid | Select alternative fibrate (fenofibrate) | | Rosuvastatin | OATP1B1/1B3 substrate | Rosuvastatin AUC ~2-fold increase | Dose cap | Max rosuvastatin 20 mg/day | | Simvastatin | CYP3A4 + OATP1B1 substrate | Simvastatin AUC increase; myopathy risk | Dose cap | Max simvastatin 20 mg/day | | Atorvastatin | OATP1B1 substrate + CYP3A4 | Moderate AUC increase projected | Monitor/Adjust | Use lowest effective dose; monitor CK if symptomatic | | Pitavastatin | OATP1B1/1B3 substrate | AUC increase expected | Monitor | Use lowest effective dose | | Pravastatin | OATP1B1/1B3 substrate | AUC increase expected | Monitor | Use lowest effective dose | | Repaglinide | Sensitive CYP2C8 substrate | AUC increases ~2- to 3-fold | Avoid or adjust | If needed, reduce repaglinide dose; monitor glucose | | Rosiglitazone | Sensitive CYP2C8 substrate | AUC increases ~2-fold | Monitor/Adjust | Use lowest effective dose; monitor for edema and fluid retention | | Paclitaxel | Sensitive CYP2C8 substrate | Increased systemic exposure | Avoid if possible | Coordinate with oncology; if necessary, monitor toxicity | | Montelukast | CYP2C8 substrate | Modest AUC increase | Monitor | Standard dosing acceptable; observe for adverse effects | | Digoxin | P-gp substrate | Digoxin plasma levels may increase | Monitor | Check digoxin level 1-2 weeks after resmetirom initiation | | Levothyroxine | THR agonism overlap | No pharmacokinetic interaction; additive pharmacodynamic TSH suppression possible | Monitor | Recheck TSH at 6-8 weeks; adjust levothyroxine if TSH falls below normal | | Warfarin | CYP2C9 substrate (minor CYP2C8 contribution to R-warfarin) | Small INR increase possible | Monitor | Check INR 7-10 days after starting resmetirom | | Oral contraceptives (ethinyl estradiol + norgestimate) | OATP1B1 substrate component | Modest exposure change; clinical significance uncertain | Monitor | No dose adjustment required but document monitoring | | Rifampin | Strong CYP2C8 inducer + OATP1B1 inducer | Resmetirom AUC decreases; reduced efficacy | Avoid | Select alternative antimycobacterial agent when possible | | Fenofibrate | Weak CYP2C8 inhibition, not OATP-dependent | Minimal effect on resmetirom | Acceptable | No dose adjustment; preferred over gemfibrozil |

1 5 6 7 8

Statin Interactions in Depth

Statins are the most consequential interaction class for resmetirom because MASH patients frequently carry dyslipidemia and are already on statin therapy before MASH treatment begins.

Why OATP1B1 Inhibition Raises Statin Risk

OATP1B1 (encoded by SLCO1B1) is the primary hepatic uptake transporter for rosuvastatin, pravastatin, pitavastatin, and (to a lesser degree) atorvastatin and simvastatin acid. 7 When OATP1B1 is inhibited, statin hepatic extraction falls and systemic plasma concentrations rise. Higher systemic statin levels correlate with skeletal muscle exposure and myopathy risk. The CPIC guideline for SLCO1B1 and statins categorizes even a 2-fold AUC increase as clinically meaningful. 9

Recommended Statin Dose Caps with Resmetirom

The Rezdiffra prescribing information specifies: 1

• Rosuvastatin: maximum 20 mg/day (down from the approved maximum of 40 mg/day)
• Simvastatin: maximum 20 mg/day (down from 80 mg/day, which is itself restricted by an FDA safety communication)
• Atorvastatin: no specific cap stated, but use the lowest effective dose with monitoring

Fluvastatin and pitavastatin dose adjustments are not specifically listed in the current label. Given their OATP1B1 dependence, applying the same caution used for rosuvastatin is reasonable pending further data. 9

Monitoring for Statin-Related Myopathy

Measure creatine kinase (CK) at baseline before starting resmetirom if the patient takes a statin. Recheck CK if the patient reports new muscle pain, weakness, or brown urine. The threshold for statin discontinuation is CK greater than 10 times the upper limit of normal with symptoms, per ACC/AHA guidance. 10

CYP2C8 Substrate Interactions in Depth

Repaglinide

Repaglinide is the classic sensitive CYP2C8 substrate used in drug interaction studies. The FDA's drug interaction guidance uses repaglinide AUC change as the benchmark for classifying CYP2C8 inhibitor potency. 6 A 2- to 3-fold repaglinide AUC increase with a moderate inhibitor translates to prolonged and amplified insulin secretion. Patients on repaglinide plus resmetirom need glucose monitoring and may require a 50% repaglinide dose reduction. If glycemic control is unstable, switching to a sulfonylurea with lower CYP2C8 dependence (glimepiride is primarily CYP2C9) may be preferable. 11

Rosiglitazone

Rosiglitazone is metabolized predominantly by CYP2C8. Resmetirom-driven inhibition may increase rosiglitazone AUC by roughly 2-fold, raising the risk of fluid retention, heart failure exacerbation, and bone fracture already associated with thiazolidinediones. 12 Given that MASH patients often have heart failure or cardiovascular disease, the combination warrants careful risk-benefit assessment. The lower-dose rosiglitazone strategy or substitution with pioglitazone (less CYP2C8-dependent) should be considered.

Paclitaxel

Paclitaxel is a sensitive CYP2C8 substrate used in cancer chemotherapy. MASH with fibrosis can coexist with cancer, particularly hepatocellular carcinoma. If paclitaxel-based regimens are necessary, oncology and hepatology should coordinate; resmetirom may need temporary interruption or paclitaxel dosing modified with toxicity monitoring. 13

Thyroid Hormone-Related Interactions

Levothyroxine Co-Prescribing

Hypothyroidism is common in the MASH population. Resmetirom does not inhibit CYP enzymes that metabolize levothyroxine, so the pharmacokinetic interaction is negligible. The concern is pharmacodynamic overlap: resmetirom activates hepatic THR-β and may modestly suppress TSH via negative feedback at higher doses. 4 A patient already titrated to a TSH target of 0.5 to 2.5 mIU/L on levothyroxine may drift below range. Recheck TSH 6 to 8 weeks after starting resmetirom and adjust levothyroxine as needed.

Methimazole and Propylthiouracil

No direct PK interaction is expected. Patients with concurrent hyperthyroidism on antithyroid drugs represent an unusual clinical scenario; any change in thyroid status will alter the pharmacodynamic background against which resmetirom acts. TSH monitoring every 8 to 12 weeks is appropriate.

Interactions Relevant to the MASH Comorbidity Field

MASH rarely presents in isolation. The typical patient carries type 2 diabetes, dyslipidemia, hypertension, and sometimes atrial fibrillation. Several drugs used in these conditions deserve individual attention.

Digoxin

Digoxin has a narrow therapeutic index. Resmetirom's P-gp inhibition in vitro raises concern for clinically meaningful digoxin accumulation, especially in patients with reduced renal function. 8 Check a digoxin level 1 to 2 weeks after initiating resmetirom and target the conventional range of 0.5 to 0.9 ng/mL for heart failure.

Warfarin

Warfarin S-enantiomer is metabolized by CYP2C9, not CYP2C8. The R-enantiomer has minor CYP2C8 dependence. A small increase in INR is possible but the magnitude is unlikely to be large. Monitor INR 7 to 10 days after starting resmetirom. The INR target does not change; the check is precautionary. 14

Oral Anticoagulants (DOACs)

Apixaban and rivaroxaban are P-gp and CYP3A4 substrates. Resmetirom's P-gp inhibition is modest in clinical context. No specific DOAC dose adjustment is listed in the current label, but clinicians should be aware that additive bleeding risk is possible if liver function deteriorates, since all DOACs require some hepatic metabolism. 15

Original Clinical Decision Framework: Resmetirom DDI Risk Stratification at Initiation

Before writing the first prescription for resmetirom, apply the following three-step DDI screen developed by the HealthRX clinical pharmacology team:

Step 1. Identify contraindicated combinations. Pull the medication list and flag cyclosporine. If present, resmetirom is contraindicated. Gemfibrozil is a strong avoid; switch to fenofibrate before resmetirom initiation.

Step 2. Apply statin dose caps. If rosuvastatin exceeds 20 mg/day, reduce before starting. If simvastatin exceeds 20 mg/day, reduce before starting. Document the rationale in the chart.

Step 3. Screen for CYP2C8-sensitive substrates. Check for repaglinide, rosiglitazone, and paclitaxel. For each, decide on dose reduction, glucose or toxicity monitoring plan, or therapeutic substitution before day 1 of resmetirom.

A structured pre-prescribing checklist reduces interaction-related adverse events by ensuring all three steps occur at initiation rather than reactively after a lab abnormality or adverse event surfaces.

Special Populations and DDI Considerations

Hepatic Impairment

Resmetirom is approved for noncirrhotic MASH (F2-F3). Patients with Child-Pugh A cirrhosis (F4) were excluded from MAESTRO-NASH. 3 Hepatic impairment reduces the clearance of resmetirom and of many co-prescribed CYP2C8 substrates simultaneously, compounding interaction risk. The prescribing information states resmetirom is not recommended in patients with decompensated cirrhosis. 1

Renal Impairment

No dose adjustment is required for mild-to-moderate renal impairment. Severe renal impairment (eGFR <30 mL/min/1.73 m²) was not adequately studied. 1 For drugs renally cleared (e.g., digoxin, metformin), declining eGFR in MASH patients will affect those drugs' levels independently of the resmetirom interaction.

Pregnancy and Hormonal Contraceptives

Resmetirom caused fetal harm in animal reproduction studies and should be avoided in pregnancy. 1 Ethinyl estradiol is an OATP1B1 substrate; modest exposure changes are projected with resmetirom co-administration but no contraceptive failure has been reported. Non-hormonal or barrier contraception does not carry this pharmacokinetic uncertainty. 16

Prescribing Summary: Key Actions Before and After Starting Resmetirom

Before Starting

1. Confirm no cyclosporine or gemfibrozil on the medication list.
2. Reduce rosuvastatin to 20 mg/day or below and simvastatin to 20 mg/day or below.
3. Review CYP2C8-sensitive antidiabetic agents (repaglinide, rosiglitazone) and make dose or drug adjustments.
4. Obtain baseline CK if any statin is co-prescribed.
5. Check baseline TSH if patient takes levothyroxine.
6. Check baseline INR if patient takes warfarin.
7. Check baseline digoxin level if patient takes digoxin.

At 6 to 8 Weeks

1. Recheck TSH in patients on levothyroxine.
2. Recheck INR in patients on warfarin.
3. Recheck digoxin level in patients on digoxin.
4. Recheck CK if any muscle symptoms have developed.
5. Recheck fasting glucose or HbA1c if repaglinide or rosiglitazone dose was adjusted.

At 24 Weeks (MAESTRO-NASH Monitoring Checkpoint)

The MAESTRO-NASH protocol assessed liver biochemistry and lipids at 24 and 52 weeks. 3 Use these time points to reassess the statin dose cap versus LDL target and adjust statin therapy if needed within the constraints of the interaction. 17