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General Description:

Nedosiran, identified by CAS number 2266591-83-5, is a notable compound with significant therapeutic applications. Nedosiran is an RNA interference targeting hepatic lactate dehydrogenase, the enzyme responsible for the conversion of glyoxylate to oxalate. Oxalate, particularly calcium oxalate, precipitation is the main cause of kidney stones formation; therefore, blocking the production of oxalate can help alleviate renal symptoms. Nedosiran was approved by the FDA on October 2^nd, 2023, under the brand name RIVFLOZA to lower urinary oxalate levels in children 9 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. This approval is based on the favorable results from the pivotal phase 2 PHYOX^TM2 and interim data from the ongoing phase 3 PHYOX^TM3 clinical trials.

Indications:

This drug is primarily indicated for: RIVFLOZA is indicated to lower urinary oxalate levels in children 9 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function, e.g, eGFR ≥ 30 mL/min/1.73 m². Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Nedosiran undergoes metabolic processing primarily in: As an antisense oligonucleotide, nedosiran is expected to be metabolized by endo- and exonucleases to shorter oligonucleotides. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Nedosiran are crucial for its therapeutic efficacy: Nedosiran exhibited a dose-proportional increase in plasma exposure following single subcutaneous doses from 1.5 to 6.0 mg/kg. Nedosiran exhibited time-independent pharmacokinetics with multiple doses of 160 mg once monthly (body weight ≥ 50 kg), 128 mg once monthly (body weight < 50 kg), or 3.3 mg/kg once monthly in the age range of 6 to 11 years. Other pharmacokinetic parameters like C_max, AUC_0-last, and T_max were calculated to be 844 ng/mL, 13600 ng*h/mL, and 6 hours respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Nedosiran is an important consideration for its dosing schedule: The half-life of nedosiran was estimated to be 15 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Nedosiran exhibits a strong affinity for binding with plasma proteins: The protein binding of nedosiran was estimated to be 85.6%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Nedosiran from the body primarily occurs through: Approximately 27% of the administered nedosiran dose is excreted unchanged into the urine within 24 hours of dosing. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Nedosiran is distributed throughout the body with a volume of distribution of: The volume of distribution was calculated to be 126 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Nedosiran is a critical factor in determining its safe and effective dosage: The clearance of nedosiran was calculated to be 5.7 L/hr. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Nedosiran exerts its therapeutic effects through: The pharmacodynamic effects of nedosiran were evaluated after single-dose and monthly-dose administration in patients with PH1. Dose-dependent reductions in urinary oxalate were observed in the single-dose range of 1.5 mg/kg to 6.0 mg/kg. With the recommended monthly dose regimen of nedosiran, the onset of the effect was observed at the first measurement (30 days after the first dose) and the effect persisted with continued monthly dosing. At the recommended dose, nedosiran does not lead to clinically relevant QT interval prolongation. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Nedosiran functions by: Nedosiran is a double-stranded siRNA, conjugated to GalNAc aminosugar residues. After subcutaneous administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes. Nedosiran reduces levels of hepatic lactate dehydrogenase (LDH) via the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran reduces the production of oxalate by the liver, thereby reducing subsequent oxalate burden. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Experimental Properties:

Further physical and chemical characteristics of Nedosiran include:

• Water Solubility: Freely soluble
• Molecular Weight: 22238.0
• Molecular Formula: C662H808F19N231O413P57S6Na57