Introduction
A considerable number of drug candidates have the potential to alter cardiovascular functions at therapeutically relevant concentrations. Predicting those effects as early as possible during drug development is critically important to ensure the progression of safer compounds through the pipeline and to minimize the risk of cardiovascular safety liabilities emerging at later stages of development (Laverty et al., 2011; Cook et al., 2014; Lester and Olbertz, 2016). The fast-paced advancements ongoing in the development of human-based in silico and in vitro predictive approaches hold great promise for improving the early detection of drug-induced cardiovascular alterations, including cardiotoxicity (Clements et al., 2015; Colatsky et al., 2016; Gintant et al., 2016; Land et al., 2017; Passini et al., 2017). However, to date, the use of in vivo preclinical models is still a key aspect of cardiovascular efficacy and safety assessment (Fliegner et al., 2015; Vargas et al., 2015; Berridge et al., 2016), mainly because of the ability of in vivo testing to capture integrated multiscale processes that cannot be observed outside an intact organism. These processes include pharmacokinetic-dependent and metabolism-mediated effects, chronic or delayed toxicity, vascular and hemodynamic alterations, as well as interaction between cardiovascular, nervous, and renal systems (Holzgrefe et al., 2014).
In this context, the identification of the most suitable preclinical animal model represents a central challenge for the design of a successful testing strategy, as this choice can profoundly affect the translational value of each experiment and, in turn, data interpretation and subsequent decision-making (Denayer et al., 2014; Holzgrefe et al., 2014). From a cardiovascular perspective, dog and nonhuman primates (e.g., cynomolgus monkey) are the most commonly used nonrodent models, as their physiology is considered the most relevant to humans (Leishman et al., 2012; Holzgrefe et al., 2014). Other test species include minipig (Bode et al., 2010), marmoset (Tabo et al., 2008), and guinea pigs (Marks et al., 2012). Beside these models, small rodent species (i.e., rat and mouse) remain the most popular choice to investigate cardiovascular physiology and disease, genetics, and pharmacology (Camacho et al., 2016). As with any animal model, each species mentioned above has both advantages and limitations (e.g., see Holzgrefe et al. (2014) and Milani-Nejad and Janssen (2014) for extensive reviews of these aspects); however, common limitations include high ethical and financial costs, and low throughput potential.
In recent years, extensive research efforts have been allocated worldwide to identify potential alternative testing approaches that may lead to the reduction, replacement, or refinement (3Rs) of the model species mentioned above. Within this research theme, the zebrafish has emerged as a new, potentially valuable, model for the in vivo assessment of a variety of human-relevant drug-induced effects, including cardiovascular alterations (Parker et al., 2014; MacRae and Peterson, 2015). Zebrafish are characterized by a number of valuable features, including relatively inexpensive maintenance costs, amenability to genetic manipulation, high conservation of human drug targets (i.e., >82%; Howe et al., 2013; Verbruggen et al., 2017), and of a broad range of human-relevant phenotypes that can be modified by pharmacological treatment (MacRae and Peterson, 2015).
Considering the high impact of unpredicted cardiotoxicity on drug development (Laverty et al., 2011), the availability of a simpler vertebrate model, such as zebrafish, may enable cardiovascular profiling of new drugs before commencing mammalian toxicity tests, thus serving as a bridge between early in vitro safety predictions and later in vivo preclinical testing. Several studies have started to explore this potential from a translational perspective, such as Parker et al. (2014)and Cornet et al. (2017). Despite encouraging results, to date, the implementation of zebrafish in existing testing strategies faces resistance not least because of uncertainty around the quantitative aspects of zebrafish cardiovascular responses compared with both mammalian preclinical species and humans. We propose that coordinated efforts to perform quantitative comparative assessment of those responses may help to clarify the translational value of zebrafish and help define its domain of applicability from both mechanistic and phenotypic standpoints.
The aim of the present study was to quantify the degree of similarity in the in vivo cardiovascular responses of zebrafish, rat, dog, and human to three model compounds (propranolol, losartan, and captopril), which act as modulators of two key systems (beta-adrenergic and renin–angiotensin systems) involved in the regulation of cardiovascular functions. To do so, we used in vivo imaging techniques to generate novel zebrafish experimental data. The latter were successively combined with a database of interspecies responses extracted from the literature to perform a meta-analysis of effect size and direction across species (Figure 1).
Link to the publication : https://www.frontiersin.org/articles/10.3389/fphar.2019.00893/full
Abstract
