Using a Systems Pharmacology Approach to Study the Effect of Statins on the Early Stage of Atherosclerosis in Humans

Abstract

More than 100,000 people have participated in controlled trials of statins (lowering cholesterol drugs) since the introduction of lovastatin in the 1980s. Meta-analyses of this data have shown that statins have a beneficial effect on treated groups compared to control groups, reducing cardiovascular risk. Inhibiting the HMG-CoA reductase in the liver, statins can reduce cholesterol levels, thus reducing LDL levels in circulation. Published data from intravascular ultrasound studies (IVUS) was used in this work to develop and validate a unique integrative system model; this consisted of analyzing control groups from two randomized controlled statins trials (24/97 subjects respectively), one treated group (40 subjects, simvastatin trial), and 27 male subjects (simvastatin, pharmacokinetic study). The model allows to simulate the pharmacokinetics of statins and its effect on the dynamics of lipoproteins (e.g., LDL) and the inflammatory pathway while simultaneously exploring the effect of flow-related variables (e.g., wall shear stress) on atherosclerosis progression.

A Six‐Stage Workflow for Robust Application of Systems Pharmacology

“…PK models (including physiologically based PK (PBPK) and population PK) can serve as inputs into models of downstream biology (e.g., refs. 60,73,74). PBPK approaches can themselves be considered QSP given the mechanistic detail included.…”

From PK/PD to QSP: Understanding the Dynamic Effect of Cholesterol-Lowering Drugs on Atherosclerosis Progression and Stratified Medicine

“…[30]. This completely novel QSP approach, in-between two different worlds (PK/PD and Systems Biology) used the mathematical model as a vehicle to understand the PK of Simvastatin and its effect on LDL and atherosclerotic plaque evolution and vascular remodeling, which is the clinical endpoint.…”

Is systems pharmacology ready to impact upon therapy development? A study on the cholesterol biosynthesis pathway

“…Industry has evaluated systems pharmacology as a tool to inform trial design in areas of cardiovascular disease, endocrinology, neurogenerative disease, respiratory disease, oncology and infectious disease (Visser et al, ) and to inform regulatory development (Visser et al, ; Peterson and Riggs, ). There have a been a number of specific studies of nerve growth factor (Benson et al, ), coagulation (Wajima et al, ), innate immunity (Madrasi et al, ), cancer (Abaan et al, ) and atherosclerosis (Pichardo–Almarza et al, ).…”