Find, compare & contact
Inclisiran API Manufacturers & Suppliers

General Description:

Inclisiran, identified by CAS number 1639324-58-5, is a notable compound with significant therapeutic applications. Inclisiran is a long-acting, synthetic small interfering RNA (siRNA) directed against proprotein convertase subtilisin-kexin type 9 (PCSK9), which is a serine protease that regulates plasma low-density lipoprotein cholesterol (LDL-C) levels. By binding to PCSK9 messenger RNA, inclisiran prevents protein translation of PCSK9, leading to decreased concentrations of PCSK9 and plasma concentrations of LDL cholesterol. Lowering circulating plasma LDL-C levels offers an additional benefit of reducing the risk of cardiovascular disease (CVD) and improving cardiovascular outcomes, as hypercholesterolemia is a major known risk factor for CVD. On December 11, 2020, the European Commission (EC) granted authorization for marketing inclisiran as the first and only approved siRNA for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, alone or in combination with other lipid-lowering therapies. Inclisiran was later approved by the FDA on December 22, 2021, for the treatment of heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease in adults. It is marketed under the trade name Leqvio.

Indications:

This drug is primarily indicated for: In Europe, inclisiran is indicated for the treatment of primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia in adults, as an adjunct to diet. It can be used in combination with a statin or statin with other lipid-lowering therapies in patients who cannot reach LDL-C goals with the maximum tolerated dose of a statin. In patients who cannot tolerate statins or in whom a statin is contraindicated, inclisiran can be used as monotherapy or in combination with other lipid-lowering therapies. In the US, inclisiran is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of lowdensity lipoprotein cholesterol (LDL-C). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Inclisiran undergoes metabolic processing primarily in: Inclisiran is metabolized by nucleases to form smaller nucleotides of varying lengths. It is not anticipated to be 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 Inclisiran are crucial for its therapeutic efficacy: After uptake into the liver, inclisiran has a long duration of action. Following subcutaneous administration of a single dose ranging from 24 mg to 756 mg, systemic exposure to inclisiran increased in a dose-proportional manner. The mean C_max was 509 ng/mL and the T_max was approximately 4 hours after the administration of 284 mg inclisiran. The mean AUC_0-inf was 7980 ng x h/mL. After 48 hours of dosing, drug plasma concentrations were undetectable. Pharmacokinetic findings following a single-dose administration of inclisiran were comparable to inclisiran administered in multiple doses. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Inclisiran is an important consideration for its dosing schedule: The terminal elimination half-life of inclisiran is approximately 9 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Inclisiran exhibits a strong affinity for binding with plasma proteins: _In vitro_, inclisiran is 87% protein bound at clinically relevant plasma concentrations. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Inclisiran from the body primarily occurs through: About 16% of the total dose of inclisiran is cleared through the kidney. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Inclisiran is distributed throughout the body with a volume of distribution of: The apparent volume of distribution was approximately 500 L following subcutaneous administration of a single 284 mg dose of inclisiran in healthy adults. According to non-clinical studies, inclisiran is highly taken up by the liver. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Inclisiran is a critical factor in determining its safe and effective dosage: There is limited information on the clearance rate of inclisiran. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Inclisiran exerts its therapeutic effects through: Inclisiran is a long-acting small interfering RNA (siRNA) that works to lower plasma LDL-cholesterol (LDL-C) levels. In clinical trials, the reduction of LDL-C levels was observed within 14 days post-dose: mean reductions of LDL-C by 48-51% were observed 30 to 60 days post-dose and reduction of LDL-C levels by 53% persisted after 180 days post-dose. In healthy volunteers, inclisiran reduced PCSK9 levels by 70-80% and LDL-C levels by 27-60%. In a clinical trial consisting of subjects with atherosclerotic cardiovascular disease with or without diabetes, inclisiran reduced LDL-C levels by 28-52%. The long-term effect of inclisiran on cardiovascular outcomes has not yet been elucidated, although reductions in the levels of LDL-C have been associated with a reduction of cardiovascular risk. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Inclisiran functions by: Low-density lipoprotein (LDL) receptors expressed on hepatocytes are responsible for the removal of circulating LDL-C from plasma via receptor-mediated endocytosis. Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a serine protease that is mainly produced by hepatocytes. It binds to LDL receptors and targets them for lysosomal degradation, thereby reducing the levels of LDL receptors, attenuating the recycling of LDL receptors, and elevating the levels of circulating plasma LDL-C. Inclisiran is conjugated to triantennary N-acetylgalactosamine carbohydrates, which can bind to asialoglycoprotein receptors expressed in the liver. Binding to asialoglycoprotein receptors facilitates the uptake of inclisiran into the hepatocytes. Once inside the hepatocyte, inclisiran binds to the RNA-induced silencing complex (RISC), which is a ribonucleoprotein complex that serves as a template for recognizing the target complementary mRNA, activate RNAse, and cleave the target mRNA. Inclisiran incorporated into the RISC allows the drug to cleave PCSK9 mRNA and prevent PCSK9 translation, thus decreasing hepatic production of PCSK9. Less PCSK9 protein available allows more LDL receptors to be recycled to the hepatic membrane for circulating LDL-C uptake. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Inclisiran is categorized under the following therapeutic classes: Antisense Elements (Genetics), Compounds used in a research, industrial, or household setting, Diagnostic Uses of Chemicals, Hypolipidemic Agents, Hypolipidemic Agents Indicated for Hyperlipidemia, Laboratory Chemicals, Lipid Modifying Agents, Lipid Modifying Agents, Plain, Lipid Regulating Agents, Molecular Probes, Non-statin Hypolipidemic Agents Indicated for Hyperlipidemia, Nucleic Acid Probes, Nucleic Acids, Nucleic Acids, Nucleotides, and Nucleosides, PCSK9 Inhibitor, Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Inhibitors, RNA, Antisense, RNA, Small Untranslated, RNA, Untranslated. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.