A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation

Area of Science:

• Pharmacology
• Cardiovascular Physiology
• Computational Biology

Background:

• Drugs can impact the cardiovascular (CV) system, leading to cardiotoxicities like arrhythmia.
• Mathematical models offer a way to describe and predict these drug-induced effects.
• Understanding CV physiology is essential for developing accurate predictive models.

Purpose of the Study:

• To provide a tutorial on cardiovascular (CV) system aspects relevant to drug development.
• To explain CV electrophysiology, safety concepts, and model development.
• To outline regulatory expectations for model-informed drug development.

Main Methods:

• Review of key biological and medical aspects of the CV system.
• Explanation of CV electrophysiology and safety concepts.
• Discussion of practical aspects of CV model development and case studies.

Main Results:

• Model-informed approaches provide valuable insights during drug development.
• Mathematical models can aid decision-making in drug discovery and development.
• Case studies illustrate project strategy and model development for decision support.

Conclusions:

• Model-informed quantitative approaches are vital for supporting nonclinical and clinical drug development.
• Understanding CV physiology and applying mathematical modeling enhances drug safety assessment.
• This tutorial equips researchers with knowledge for effective CV safety evaluation in drug development.