Drug efficacy and safety
Mitochondrial drug effects
Mitochondrial defects are associated with severe pathophysiological conditions affecting a great variety of organs and tissues. By using a systems pharmacology approach that focuses on whole-animal testing, we aim to develop drugs for balanced pathway modulation, with improved efficacy and low toxicity. In vitro models with increasing complexity, including human cell lines, 3D tissue culture/organ models, are used to identify new drug targets. Promising compounds are further investigated in whole animal disease models to both explore the mechanisms of action and to identify an optimal pharmacodynamic and pharmacokinetic profile in vivo.
A second line of research is focused on adverse bioenergetic effects of drugs. Drug-induced mitochondrial dysfunction is a major contributor to adverse reactions of pharmaceuticals. Attempts to predict mitochondrial toxicity have been unsuccessful because they have focussed on single pathways rather than the mechanisms by which drugs can interfere with the coordinated regulation of cell bioenergetics. We aim to integrate in vitro and in vivo effects of drugs that lead to mitochondrial alterations into physiologically-based pharmacokinetic and -dynamic models to translate findings from animal studies to clinical implications on drug efficacy and safety.