M1 ( Ki = 0.42 nM ); M2 ( Ki = 0.32 nM ); M3 ( Ki = 0.18 nM ); M4 ( Ki = 0.56 nM ); M5 ( Ki = 6.7 nM )

Revefenacin, tiotropium, and glycopyrronium together produce a prolonged inhibition of acetylcholine-induced bronchoconstriction in anesthetized dogs that lasts for up to twenty-four hours. Inhaled revefenacin protects anesthetized rats from methacholine-induced bronchoconstriction for 24 hours in a dose-dependent manner. After seven days of once-daily dosing, the bronchoprotective potencies are maintained, with an estimated 24-hour potency of 45.0 µg/mL[2].

Rats: Rats are exposed by inhaling a nebulized solution of either vehicle (sterile water) or revefenacin (3–3000 µg/mL), tiotropium (0.3–300 µg/mL), or glycopyrronium (1–1000 µg/mL) to ascertain the bronchoprotective and antisialagogue potency after a single dose. 24 hours after the dosage, bronchoprotective activity is evaluated. The antisialagogue effect's peak effect time is determined by measuring the inhibition of Pilo 1, 6, or 12 hours after an effective dose of the test compound was inhaled. At this point in time, all subsequent doses are measured[2].

Absorption, Distribution and Excretion
In pharmacokinetic studies, remifenacin was rapidly absorbed with a linear increase in plasma exposure, with Cmax, tmax, and AUC ranging from 0.02–0.15 ng/ml, 0.48–0.51 h, and 0.03–0.36 ng·h/ml, respectively. Remifenacin exhibits very limited bioaccumulation, reaching steady state on day 7. After reaching maximum concentration, remifenacin concentrations show a biphasic decline. This elimination kinetics is characterized by a rapid decrease in plasma concentration followed by a slow, apparent biexponential elimination. Renal elimination of remifenacin is limited, with an average cumulative excretion in the urine of less than 0.2% of the administered dose as unchanged drug. Following intravenous administration, 54% of the dose was excreted in feces and 27% in urine, demonstrating its high hepatobiliary metabolic efficiency.
The reported volume of distribution after intravenous administration of remifenacin is 218 liters, indicating its widespread distribution in tissues.
Renal clearance of remifenacin is negligible; therefore, clearance is not a primary parameter for this drug.
Metabolism/Metabolites

Remifenacin exhibits high metabolic activity and undergoes rapid metabolic turnover after distribution from the lungs. This metabolic process primarily involves enzymatic hydrolysis by CYP2D6, producing its major hydrolytic metabolite THRX-195518.
Biological Half-Life

The apparent terminal half-life of 350 μg of remifenacin is 22.3–70 hours.

Hepatotoxicity
As with other anticholinergic drugs, remifenacin has not been found to be associated with elevated liver enzymes or clinically significant liver injury. Another reason for its high hepatotoxicity may be its low systemic absorption rate when administered via inhalation. Probability Score: E (Unlikely to cause clinically significant liver injury). Drug Category: Anticholinergic Drug

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Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation There is currently no information regarding the use of remifenacin during lactation. Since the oral absorption rate is only 3%, it is unlikely to affect breastfed infants. Prolonged use of remifenacin may reduce milk production or the milk ejection reflex. With prolonged use, signs of reduced milk production (e.g., dissatisfaction, poor weight gain) should be observed. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found. ◉ Effects on Lactation and Breast Milk As of the revision date, no relevant published information was found.

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Protein binding
The protein binding rates of remifenac and its active metabolite are 71% and 42%, respectively.

[1]. In vitro characterization of TD-4208, a lung-selective and long-acting muscarinic antagonist bronchodilator (Abstract). Am J Respir Crit Care Med 179:A4553.

[2]. In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models. J Pharmacol Exp Ther. 2013 Aug;346(2):241-50.

Remifenac is a novel tertiary amine biphenyl carbamate drug belonging to the long-acting muscarinic receptor antagonist (LAMA) family. Its unstable primary amide group forms a "soft drug site," allowing for rapid systemic clearance and minimizing systemic adverse reactions. LAMAs belong to the parent class of long-acting inhaled bronchodilators, recommended for maintenance therapy of chronic obstructive pulmonary disease (COPD). Remifenac is the first once-daily nebulized LAMA treatment in the LAMA family. It was developed by Theravance Biopharma and approved by the FDA on November 9, 2018. Remifenac is an anticholinergic drug. Its mechanism of action is as a cholinergic antagonist. Remifenac is a synthetic anticholinergic drug, administered once daily via nebulization for maintenance therapy in patients with chronic obstructive pulmonary disease. Remifenac does not cause elevated liver enzymes or clinically significant acute liver injury.

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Drug Indications
Remifenacin is indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD) and is administered as an inhaled solution. COPD is a rapidly developing disease and the third leading cause of death in the United States. The disease is characterized by airflow limitation that is not fully reversible.
FDA Label

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Mechanism of Action
Remifenacin is an inhaled bronchodilator, a muscarinic receptor antagonist, with a long-acting bronchodilatory effect. Studies have shown that remifenacin has a high affinity for all five muscarinic cholinergic receptors and exhibits competitive antagonism. Studies have also shown that remifenacin dissociates significantly more slowly from the M3 muscarinic receptor (hM3) compared to the M2 receptor (hM2), indicating kinetic selectivity for this subtype. This competitive antagonism inhibits acetylcholine-induced airway tissue calcium mobilization and contractile responses.
Furthermore, due to its long-lasting bronchodilatory effect, remifenacin is considered a long-acting muscarinic receptor antagonist and can therefore be administered once daily. This effect is crucial for the treatment of chronic obstructive pulmonary disease (COPD), as the primary goal of treatment is to reduce the frequency and severity of acute exacerbations, which are typically caused by increased cholinergic bronchodilatory tone mediated by muscarinic receptors on the parasympathetic ganglia and airway smooth muscle. Therefore, remifenacin's activity effectively and persistently protects the bronchi from the effects of acetylcholine or methacholine-induced bronchoconstrictive responses.

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Pharmacodynamics
Remifenacin has been reported to produce a sustained, long-lasting bronchodilatory effect with low levels of antimuscarinic side effects. Clinical trials have demonstrated that remifenacin has a long duration of action and low systemic exposure in patients with COPD. Furthermore, reports indicate that a dose of 88 micrograms can produce a clinically effective bronchodilator effect, which can be assessed by forced expiratory volume in one second (FEV1) and continuous pulmonary function testing. In placebo-controlled trials, remifenacin reduced the use of salbutamol emergency inhalers and consistently increased peak expiratory flow, reaching its peak on day 7 and remaining stable. Additionally, remifenacin has been reported to have a superior lung selectivity index and a reduced salivation-promoting effect compared to other long-acting anticholinergic drugs such as glycopyrronium and tiotropium.

C35H43N5O4

597.76

597.331

C, 70.33; H, 7.25; N, 11.72; O, 10.71

864750-70-9

864750-70-9; 864751-51-9 (phosphate); 864751-53-1 (sulfate); 864751-55-3 (oxalate)

11753673

White to off-white solid powder

1.3±0.1 g/cm3

777.5±60.0 °C at 760 mmHg

424.0±32.9 °C

0.0±2.7 mmHg at 25°C

1.645

3.22

2

6

11

44

918

0

O=C(NC1C(C2C=CC=CC=2)=CC=CC=1)OC1CCN(CCN(C)C(C2C=CC(CN3CCC(C(N)=O)CC3)=CC=2)=O)CC1

FYDWDCIFZSGNBU-UHFFFAOYSA-N

InChI=1S/C35H43N5O4/c1-38(34(42)29-13-11-26(12-14-29)25-40-19-15-28(16-20-40)33(36)41)23-24-39-21-17-30(18-22-39)44-35(43)37-32-10-6-5-9-31(32)27-7-3-2-4-8-27/h2-14,28,30H,15-25H2,1H3,(H2,36,41)(H,37,43)

[1-[2-[[4-[(4-carbamoylpiperidin-1-yl)methyl]benzoyl]-methylamino]ethyl]piperidin-4-yl] N-(2-phenylphenyl)carbamate

TD-4208; TD4208; GSK-1160724; GSK-1160724; TD 4208; GSK1160724; trade name: Yupelri; TD-4208; GSK 1160724

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)