Multiscale modeling of drug-induced toxicity in humans

Thiel, Christoph Werner Josef; Blank, Lars Mathias (Thesis advisor); Sáez Rodríguez, Julio (Thesis advisor)

Aachen (2017)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2017

Abstract

Drug toxicity poses a crucial problem in drug development and particularly in clinical care and in publichealth. Although in vitro experiments can obtain valuable information of the mechanisms underlyingdrug-induced toxicity, there is still a clear lack of approaches translating such in vitro findings into apatient situation. In this thesis, a novel translational approach is presented and is successfully applied inthree different studies to investigate the onset of adverse drug events at patient level. Here, multiscalemodeling enables the coupling of in vitro concentration-response relationships, at the cellular level, withdrug concentration-time profiles, at the organism level, to predict cellular responses following drug administrationof different doses in vivo. The application of the developed translational approach allowedstudying drug-induced toxicity in humans (i) for acute and chronic administration of azathioprine in aproof-of-concept study, (ii) for fifteen hepatotoxic drugs in a comparative manner focusing on drug administrationof therapeutic and toxic doses, and (iii) for a drug combination therapy of acetaminophenand caffeine. The presented translational approach may lead to useful knowledge for clinical applicationgained from in vitro experiments thereby contributing to the ongoing discussion of the predictive valueof preclinical research. Overall, the results shown here provide novel insights into drug-induced toxicitywithin a patient context and, thus, may improve patient safety in drug development.