Translational Population‐Pharmacodynamic Modeling of a Novel Long‐Acting siRNA Therapy, Inclisiran, for the Treatment of Hypercholesterolemia
Abstract
Inclisiran is a novel N-acetylgalactosamine (GalNAc) conjugated small-interfering ribonucleic acid (siRNA) therapy designed to specifically target proprotein convertase subtilisin/kexin type 9 (PCSK9) mRNA in the liver for the treatment of hypercholesterolemia. Inclisiran's GalNAc attachment results in a rapid uptake into the liver, and thus a short plasma half-life, but long duration of effects on PCSK9 inhibition and low-density lipoprotein cholesterol (LDL-C) lowering. The effects on PCSK9 inhibition and consequent LDL-C reduction are sustained for more than 6 months following a single subcutaneous (s.c.) dose, despite inclisiran being detectable in the plasma only for up to 48 hours. A kinetic-pharmacodynamic (K-PD) model was developed to characterize inclisiran's dose-related LDL-C lowering effects and to evaluate the impact of intrinsic and extrinsic factors on LDL-C lowering. To accommodate the long duration of action, the K-PD model incorporated an effect compartment which represents the liver. Inclisiran concentration in the liver leads to decreased production of the PCSK9 protein and allow recycling of more LDL-C receptors on the hepatocyte cell surface, which results in a reduction of circulating LDL-C. The analysis of covariates identified PCSK9 and LDL-C baseline levels as important factors for the effects of LDL-C lowering. Observations and modeling and simulation results demonstrated that PCSK9 and LDL-C reductions are achieved rapidly after dosing and sustaine…
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The pharmacodynamic effects of inclisiran lead to an extended suppression of plasma PCSK9 levels, which directly correlates with significant LDL-C reduction.
“The pharmacodynamic effects of Inclisiran lead to an extended suppression of plasma PCSK9 levels which directly correlates with significant LDL-C reduction [71].”
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- Authors
- Gosselin, N. H., Schuck, V. J. A., Barriere, O., Kulmatycki, K., Margolskee, A., Smith, P., & He, Y.
- Affiliations
- Certara (United States) (US)
- Certara Cambridge Massachusetts USA
- Novartis Institute for Biomedical Research Cambridge Massachusetts USA
- Corresponding author
- Gosselin, Nathalie H.
- ORCID
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2022-11-14
- Volume
- 113
- Issue
- 2
- Pages
- 328-338
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W4307228097
- Cited by
- 17
- References
- 17
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 4 · 2023: 1
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- inclisiran, hypercholesterolemia, PCSK9 inhibition, LDL cholesterol lowering, siRNA therapeutics, GalNAc conjugation, effect compartment, long-acting drugs, covariate analysis
- MeSH terms
- Proprotein Convertase 9, Anticholesteremic Agents, Humans, Hypercholesterolemia, Cholesterol, LDL, RNA, Small Interfering
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