RESUMEN
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.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Sistema Cardiovascular/efectos de los fármacos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Preparaciones Farmacéuticas/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Perros , Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos , Cobayas , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Macaca mulatta , Conejos , RatasRESUMEN
BACKGROUND AND PURPOSE: Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. EXPERIMENTAL APPROACH: Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. KEY RESULTS: Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Nav 1.5 block (3-7%) and Cav 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3-4.6% and PR 2.3-10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. CONCLUSION AND IMPLICATIONS: Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies.
Asunto(s)
Antiarrítmicos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Modelos Biológicos , Animales , Compuestos de Azabiciclo/farmacología , Carbamatos/farmacología , Perros , Evaluación Preclínica de Medicamentos , Electrocardiografía , Flecainida/farmacología , Cobayas , Corazón/efectos de los fármacos , Corazón/fisiología , Humanos , Síndrome de QT Prolongado/inducido químicamente , Masculino , Quinidina/farmacología , Verapamilo/farmacologíaRESUMEN
Systems pharmacology modeling and pharmacokinetic-pharmacodynamic (PK/PD) analysis of drug-induced effects on cardiovascular (CV) function plays a crucial role in understanding the safety risk of new drugs. The aim of this review is to outline the current modeling and simulation (M&S) approaches to describe and translate drug-induced CV effects, with an emphasis on how this impacts drug safety assessment. Current limitations are highlighted and recommendations are made for future effort in this vital area of drug research.