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

Abstract

Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.

Concentration‐QT modelling shows no evidence of clinically significant QT interval prolongation with capivasertib at expected therapeutic concentrations

“…Exploratory data analysis was performed in two steps according to a prespecified exposure–response analysis plan, as outlined by the International Conference on Harmonisation (ICH) E14 guidance, the ICH implementation working group questions and answers (R3), the concentration‐QT whitepaper and in line with model‐informed approaches to cardiovascular safety. 19 , 20 , 21 , 22 First, categorical evaluation of QTc, PR and QRS intervals was performed to identify patients with significant treatment‐emergent QTc, PR and QRS prolongation (QTc: ≥450, ≥480, and ≥500 ms; ΔQTc: ≥30 and ≥60 ms; PR: ≥200 ms; QRS: ≥110 ms). Second, exploratory graphical analysis was performed to check assumptions of a prespecified linear mixed‐effects (LME) model and justify application of the model to the given data set (Figures S1 –S4 in the Supporting Information).…”

Unveiling the Multifaceted Problems Associated with Dysrhythmia

“…Gastric dysrhythmias are associated with a variety of clinical disorders, some of which may contribute to the production of nausea and vomiting. With diabetic gastroparesis, tachygastria and bradygastria can develop in up to 70% of patients [ 27 ]. Some diabetics show concurrent loss of the increase in signal amplitude typically seen with meal eating in addition to electrocardiogram rhythm abnormalities.…”

KV11.1, NaV1.5, and CaV1.2 Transporter Proteins as Antitarget for Drug Cardiotoxicity

“…Additionally, it has been estimated that approximately 2-3% of all drug prescriptions involve medications that may unintentionally cause long QT syndrome [12]. The first drugs that were removed from clinical use due to cardiotoxicity were encainide (proarrhthmic effect) and terodiline (QT interval prolongation) (Figure 1) [13,14]. Terdynafine, cisaprid, astemizole, sertindol, thoridazine, grepafloxacin have been removed due to heart toxicity [15] (Figure 1).…”