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General Description:

Lumasiran, identified by CAS number 1834610-13-7, is a notable compound with significant therapeutic applications. Lumasiran is a small interfering RNA used in the treatment of primary hyperoxaluria type 1 (PH1). This condition, caused by a deficiency in the enzyme alanine-glyoxylate aminotransferase, leads to an accumulation of oxalate, causing calcium crystal formation. These patients experience frequent kidney stones, nephrocalcinosis, and renal failure. Oxlumo, producted by Alnylam Pharmaceuticals, represents the first approved treatment for PH1. Prior to this approval, therapy consisted of symptomatic treatment such as hyperhydration, inhibitors of crystallization, , and renal transplant. Lumasiran was granted FDA approval on 23 November 2020.

Indications:

This drug is primarily indicated for: Lumasiran is indicated for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary and plasma oxalate levels in pediatric and adult patients. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lumasiran undergoes metabolic processing primarily in: Lumasiran is metabolized to smaller oligonucleotides by endo- and exonucleases. The sense strand is less prone to metabolism due to protection by the GalNac group at the 3' end. Lumasiran weakly inhibits CYP2C8 with an IC₅₀ of 461 µM, 14000 times pharmacologically relevant concentrations. It is not a substrate or inducer of any CYP450 enzymes. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lumasiran are crucial for its therapeutic efficacy: In patients ≥20 kg; a 3 mg/kg subcutaneous dose of lumasiran reacheas a C_max of 529 ng/mL, with a T_max of 4.0 hours, and an AUC of 7400 ng\*h/mL. In patients <20 kg; a 6 mg/kg subcutaneous dose of lumasiran reaches a C_max of 912 ng/mL and an AUC of 7960 ng\*h/mL. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lumasiran is an important consideration for its dosing schedule: The mean terminal half life of lumasiran is 5.2 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lumasiran exhibits a strong affinity for binding with plasma proteins: Lumasiran is 77% to 85% bound to protein in plasma. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lumasiran from the body primarily occurs through: 7-26% of a dose of lumasiran is recovered in the urine as the unmetabolized parent compound. A radiolabelled dose administered to rats was 19.5% recovered in urine and 33.9% recovered in feces. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lumasiran is distributed throughout the body with a volume of distribution of: The apparent central volume of distribution based on population estimate is 4.9 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Lumasiran is a critical factor in determining its safe and effective dosage: The apparent plasma clearance of lumasiran based on population estimate is 26.5 L/h for an average 70 kg adult. The mean renal clearance is 2.0-3.4 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Lumasiran exerts its therapeutic effects through: Lumasiran is a small interfering RNA that prevents the translation of glycolate oxidase, which reduces levels of glyoxylate, reducing metabolism of glyoxylate to oxalate. The duration of action is long as it is given every 3 months. Patients should be counselled regarding the risk of worsening metabolic acidosis in severe or end stage renal disease, as well as potentially decreased efficacy in moderate to severe hepatic impairment. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lumasiran functions by: Patients with primary hyperoxaluria type 1 produce an excess of oxalate due to a deficiency in the enzyme alanine-glyoxylate aminotransferase. Lumasiran is a small interfering RNA that silences the gene hydroxyacid oxidase 1 (HOA1). Lumasiran targets HOA1 mRNA, preventing translation to the enzyme glycolate oxidase (GO). Reduced levels of GO, reduce levels of glyoxylate, leaving less reactants available for metabolism to oxalate. In the ILLUMINATE trials, lumasiran reduced oxalate levels in 84% of adults and children over 6 years to at or below 1.5 times the upper limits of normal. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Lumasiran is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Antisense Elements (Genetics), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (weak), Cytochrome P-450 Enzyme Inhibitors, Genitourinary Agents, HAO1-directed Small Interfering Ribonucleic Acid (siRNA), Nucleic Acids, Nucleic Acids, Nucleotides, and Nucleosides, Renal Agents, RNA, Antisense, RNA, Small Untranslated, RNA, Untranslated, Small Interfering RNA, Various Alimentary Tract and Metabolism Products. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lumasiran include:

• Water Solubility: 387 mg/mL
• Molecular Weight: 16338.54
• Molecular Formula: C530H712F10N173O320P43S6