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General Description:

Revefenacin, identified by CAS number 864750-70-9, is a notable compound with significant therapeutic applications. Revefenacin is a novel biphenyl carbamate tertiary amine agent that belongs to the family of the long-acting muscarinic antagonists (LAMA). The labile primary amide in the structure produces a "soft-drug" site that allows rapid systemic clearance and minimizing of the systemically mediated adverse reactions. The LAMA group falls into a parent category known as long-acting inhaled bronchodilators and this type of agents are recommended as a maintenance therapy for chronic obstructive pulmonary disease (COPD). From the LAMA group, revefenacin is the first once-daily nebulized LAMA treatment. It was developed by Theravance Biopharma and FDA approved on November 9, 2018.

Indications:

This drug is primarily indicated for: Revefenacin is indicated as an inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). COPD is a growing disease being the third leading cause of death in the US. This disease is characterized by not fully reversible airflow limitation. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Revefenacin undergoes metabolic processing primarily in: Revefenacin presents a high metabolic liability producing a rapid metabolic turnover after being distributed from the lung. This metabolic process is done primarily via enzymatic hydrolysis via CYP2D6 to its major hydrolytic metabolite THRX-195518. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Revefenacin are crucial for its therapeutic efficacy: In pharmacokinetic studies, revefenacin was absorbed very rapidly and presented a linear increase in plasma exposure with Cmax, tmax and AUC that ranged between 0.02-0.15 ng/ml, 0.48-0.51 hours and 0.03-0.36 ng.h/ml, respectively. The bioaccumulation of revefenacin was very limited and the steady-state was achieved by day 7. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Revefenacin is an important consideration for its dosing schedule: The apparent terminal half-life of a dose of 350 mcg of revefenacin was 22.3-70 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Revefenacin exhibits a strong affinity for binding with plasma proteins: The protein binding of revefenacin and its active metabolite is of 71% and 42% respectively. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Revefenacin from the body primarily occurs through: After reaching maximum concentration, revefenacin concentrations decline in a biphasic manner. This elimination kinetics is observed by a rapid declining plasma concentration followed by a slow apparent bi-exponential elimination. Renal elimination of revefenacin is limited and it presents a mean cumulative amount excreted in urine as the unchanged drug of < 0.2% of the administered dose. Following intravenous revefenacin administration, 54% of the dose is recovered in feces and 27% was recovered in urine which confirms a high hepatobiliary processing. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Revefenacin is distributed throughout the body with a volume of distribution of: After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Revefenacin is a critical factor in determining its safe and effective dosage: The renal clearance of revefenacin is negligible and thus, the clearance rate is not a major parameter for this drug. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Revefenacin exerts its therapeutic effects through: Revefenacin has been reported to produce a sustained, long-acting bronchodilation with lower anti-muscarinic-related side effects. In clinical trials, revefenacin demonstrated to be of a long duration of action and low systemic exposure in patients with COPD. Also, it was reported that a dose of 88 mcg can produce a clinically effective bronchodilation measured by through forced expiratory volume in 1s and serial spirometric assessments. In placebo-controlled trials, revefenacin showed a decrease in the use of albuterol rescue inhalers and sustained increases in the peak expiratory flow rate that reached a steady state at a maximum in day 7. As well, there was a reported superior lung selectivity index when compared with other LAMAs such as glycopyrronium and tiotropium which produced a decreased sialagogue effect. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Revefenacin functions by: Revefenacin is an inhaled bronchodilator muscarinic antagonist with a long-acting bronchodilation activity. It has been shown to present a high affinity and behaved as a competitive antagonist of the five muscarinic cholinergic receptors. Studies have indicated that revefenacin dissociates significantly slower from the muscarinic receptor M3 (hM3) when compared to the receptor M2 (hM2) which indicates a kinetic selectivity for this subtype. This competitive antagonism produces a suppressive action of the acetylcholine-evoked calcium mobilization and contractile responses in the airway tissue. Lastly, due to the duration of the bronchodilation, revefenacin is considered a long-acting muscarinic antagonist which allows it to be dosed once daily. This response is very important for the therapy of COPD as the main goal is the reduce the frequency and severity of exacerbations which are normally driven by the presence of elevated cholinergic bronchoconstrictor tone mediated by muscarinic receptors on parasympathetic ganglia and airway smooth muscle. Hence, the activity of revefenacin produces a potent and long-lasting protection against the bronchoconstrictor response to acetylcholine or methacholine. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Revefenacin belongs to the class of organic compounds known as n-benzylpiperidines. These are heterocyclic Compounds containing a piperidine ring conjugated to a benzyl group through one nitrogen ring atom, classified under the direct parent group N-benzylpiperidines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Piperidines class, specifically within the Benzylpiperidines subclass.

Categories:

Revefenacin is categorized under the following therapeutic classes: Amides, Anticholinergic Agents, BCRP/ABCG2 Substrates, Benzene Derivatives, Bronchodilator Agents, Cytochrome P-450 CYP2D6 Substrates, Cytochrome P-450 Substrates, Drugs for Obstructive Airway Diseases, Muscarinic Antagonists, OATP1B1/SLCO1B1 Substrates, OATP1B3 substrates, P-glycoprotein substrates. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Revefenacin include:

• Water Solubility:< 1 mg/ml
• Boiling Point: 777.5 ºC at 760 mmHg
• logP: 3.22