ArticleJournal of lipid research2019
Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia.
Article in Journal of lipid research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Recent applications of quantitative systems pharmacology and machine learning models across diseases.Journal of pharmacokinetics and pharmacodynamics · 2022Pooled it
- Pharmacokinetic/Pharmacodynamic Translation and Model-Informed Drug Development for Oligonucleotide Therapeutics.Journal of clinical pharmacology · 2026Review
- Integrated Physiologically-Based Pharmacokinetic Model with a Quantitative Systems Pharmacology and Toxicology Model for Statins in Disease Population. Part 1: Model Development and Validation.The AAPS journal · 2025Article
- Credibility assessment of a mechanistic model of atherosclerosis to predict cardiovascular outcomes under lipid-lowering therapy.NPJ digital medicine · 2025Article
- A case-study of model-informed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II.CPT: pharmacometrics & systems pharmacology · 2022Article
- Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review.Journal of clinical medicine · 2022Review
- A mathematical model of in vitro hepatocellular cholesterol and lipoprotein metabolism for hyperlipidemia therapy.PloS one · 2022Article
- A quantitative systems pharmacology modeling platform for evaluating triglyceride profiles in patients with high triglycerides receiving evinacumab.CPT: pharmacometrics & systems pharmacology · 2021Article
- A Perspective on Quantitative Systems Pharmacology Applications to Clinical Drug Development.CPT: pharmacometrics & systems pharmacology · 2020Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional ∼20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.