Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes

Abstract

One contribution of 12 to a theme issue 'The Human Physiome: a necessary key to the creative destruction of medicine'. We are currently in the middle of a major shift in biomedical research: unprecedented and rapidly growing amounts of data may be obtained today, from in vitro, in vivo and clinical studies, at molecular, physiological and clinical levels. To make use of these large-scale, multi-level datasets, corresponding multi-level mathematical models are needed, i.e. models that simultaneously capture multiple layers of the biological, physiological and disease-level organization (also referred to as quantitative systems pharmacology-QSP-models). However, today's multi-level models are not yet embedded in end-usage applications, neither in drug research and development nor in the clinic. Given the expectations and claims made historically, this seemingly slow adoption may seem surprising. Therefore, we herein consider a specific example-type 2 diabetes-and critically review the current status and identify key remaining steps for these models to become mainstream in the future. This overview reveals how, today, we may use models to ask scientific questions concerning, e.g., the cellular origin of insulin resistance, and how this translates to the whole-body level and short-term meal responses. However, before these multi-level models can become truly useful, they need to be linked with the capabilities of other important existing models, in order to make them 'personalized' (e.g. specific to certain patient phenotypes) and capable of describing long-term disease progression. To be useful in drug development, it is also critical that the developed models and their underlying data and assumptions are easily accessible. For clinical end-usage, in addition, model links to decisionsupport systems combined with the engagement of other disciplines are needed to create user-friendly and cost-efficient software packages.

Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop

“…While efforts are made to develop QSP models for adult T2D, these models are not yet suitable for extrapolation to youth with T2D primarily because of the lack of complementary primary data in youth creating gaps resulting in high uncertainties when using these models. For example, T2D disease progression represented by insulin resistance, plasma glucose, and insulin production is often depicted as static from ages 0 to 20 years, ignoring the pediatric population and the unique time scale and progression it encompasses …”

A systems biology analysis of adrenergically stimulated adiponectin exocytosis in white adipocytes

“…An exciting way forward is to bring our model into the larger picture of the whole-body energy homeostasis, to both increase our understanding of normal physiology, and to acquire new knowledge of how adipose tissue dysfunction is connected to the development of type 2 diabetes and its associated comorbidities. Such advances can be done by combining our model with existing models at the molecular, organ and whole-body level (18)(19)(20).…”

Quantitative Systems Pharmacology: An Exemplar Model‐Building Workflow With Applications in Cardiovascular, Metabolic, and Oncology Drug Development

“…In brief, this model describes the hemodynamics of blood flow through the kidney, filtration and reabsorption of substances along the nephron, the resulting whole‐body balance of fluid and electrolytes, the distribution of body fluid and sodium between the blood and interstitium, systemic blood pressure, and the neurohormonal systems regulating these processes—including the renin‐angiotensin‐aldosterone system (RAAS) . The process of QSP drug‐disease model development has been described elsewhere . Here we focus on the application of the presented workflow for using an existing QSP drug‐disease model for a new application.…”

“…46 The process of QSP drug-disease model development has been described elsewhere. 5,47 Here we focus on the application of the presented workflow for using an existing QSP drug-disease model for a new application.…”