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General Description:

Difelikefalin, identified by CAS number 1024828-77-0, is a notable compound with significant therapeutic applications. Difelikefalin (CR845) is an agonist of kappa opioid receptors (KORs) useful in the treatment of pruritus secondary to chronic kidney disease. KORs were first associated with itching in 1984. Further investigations revealed that dynorphins, endogenous agonists of KORs, work to inhibit the itching sensation at the spinal cord level, and scratching could be elicited in mouse models with the administration of KOR antagonists. These revelations led to the study of KOR agonists as a potential treatment option in patients suffering from pruritic conditions. Pruritus associated with chronic kidney disease (also called uremic pruritus) affects 50-60% of all patients on dialysis and 25% of non-dialysis patients with chronic kidney disease. The clinical burden of uremic pruritus in this patient population is being increasingly recognized as contributing to a significant reduction in patient quality of life, poor outcomes, and even mortality. Options for therapy are limited - with no FDA-approved treatments, off-label was the most evidence-based and widely available treatment. Difelikefalin received FDA approval in August 2021 (under the brand name Korsuva), becoming the first FDA-approved therapy for patients with chronic kidney disease suffering from uremic pruritus. Difelikefalin was later approved by the EMA in April 2022 for the same indication.

Indications:

This drug is primarily indicated for: Difelikefalin is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP; uremic pruritus) in adults undergoing hemodialysis. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Difelikefalin undergoes metabolic processing primarily in: Difelikefalin is not metabolized to any appreciable extent and is not a substrate for cytochrome P450 enzymes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Difelikefalin are crucial for its therapeutic efficacy: Difelikefalin is administered via bolus intravenous injection with each hemodialysis treatment - for this reason, each dose is effectively 100% bioavailable. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Difelikefalin is an important consideration for its dosing schedule: The half-life of difelikefalin in hemodialysis patients prior to dialysis ranges between 23 and 31 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Difelikefalin exhibits a strong affinity for binding with plasma proteins: Difelikefalin is approximately 23-28% protein-bound in plasma, although the specific proteins to which it binds are unclear. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Difelikefalin from the body primarily occurs through: Following intravenous difelikefalin administration to hemodialysis patients, approximately 11% of the dose was excreted in the urine, 59% in the feces, and 20% in the dialysate. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Difelikefalin is distributed throughout the body with a volume of distribution of: The mean volume of distribution of difelikefalin is approximately 238 mL/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Difelikefalin is a critical factor in determining its safe and effective dosage: One cycle of hemodialysis reduces difelikefalin plasma concentrations by 70-80% and no detectable drug remains after two cycles. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Difelikefalin exerts its therapeutic effects through: Difelikefalin is administered to patients undergoing hemodialysis for chronic kidney disease (CKD) to prevent and treat the pruritus often associated with CKD. It is administered via bolus intravenous injection at the end of each hemodialysis treatment. As it works on opioid receptors, difelikefalin can cause dizziness, somnolence, and other CNS depressant effects that may impair mental or physical abilities - as such, patients should be advised to avoid operating dangerous machinery until the effect of difelikefalin on that patient is known. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Difelikefalin functions by: Difelikefalin is a synthetic peptide and agonist of kappa opioid receptors (KORs), which have long been known to be involved with the itching sensation (in addition to playing some role in addiction). Endogenous KOR agonists - called dynorphins - have a neuroinhibitory effect on the itching sensation at the spinal cord level and mouse models have shown KOR agonist antipruritic activity when used to treat itching induced by different pruritogens. Although the specifics of the mechanism have yet to be elucidated, the administration of KOR agonists, like difelikefalin, in patients with uremic pruritus has proven an effective means to suppress scratching and improve their quality of life. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Difelikefalin belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds, classified under the direct parent group Oligopeptides. This compound is a part of the Organic compounds, falling under the Organic acids and derivatives superclass, and categorized within the Carboxylic acids and derivatives class, specifically within the Amino acids, peptides, and analogues subclass.

Experimental Properties:

Further physical and chemical characteristics of Difelikefalin include:

• Water Solubility: Soluble