Model-based contextualization of in vitro toxicity data quantitatively predicts in vivo drug response in patients

Abstract

Understanding central mechanisms underlying drug-induced toxicity plays a crucial role in drug development and drug safety. However, a translation of cellular in vitro findings to an actual in vivo context remains challenging. Here, physiologically based pharmacokinetic (PBPK) modeling was used for in vivo contextualization of in vitro toxicity data (PICD) to quantitatively predict in vivo drug response over time by integrating multiple levels of biological organization. Explicitly, in vitro toxicity data at the cellular level were integrated into whole-body PBPK models at the organism level by coupling in vitro drug exposure with in vivo drug concentration–time profiles simulated in the extracellular environment within the organ. PICD was exemplarily applied on the hepatotoxicant azathioprine to quantitatively predict in vivo drug response of perturbed biological pathways and cellular processes in rats and humans. The predictive accuracy of PICD was assessed by comparing in vivo drug response predicted for rats with observed in vivo measurements. To demonstrate clinical applicability of PICD, in vivo drug responses of a critical toxicity-related pathway were predicted for eight patients following acute azathioprine overdoses. Moreover, acute liver failure after multiple dosing of azathioprine was investigated in a patient case study by use of own clinical data. Simulated pharmacokinetic profiles were therefore related to in vivo drug response predicted for genes associated with observed clinical symptoms and to clinical biomarkers measured in vivo. PICD provides a generic platform to investigate drug-induced toxicity at a patient level and thus may facilitate individualized risk assessment during drug development.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1723-x) contains supplementary material, which is available to authorized users.

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

“…The previously established multiscale approach PICD allows a quantitative description of drug-induced toxicity at patient level 14 (Figure 1) by coupling whole-body PBPK models ( Figure 2) with in vitro toxicity data from Open TG-GATEs, 28 an exceptional large-scale toxicogenomics database. In this study, PD responses were analyzed at 8 hours and 24 hours because in vitro response data for CAF had only been measured at these timepoints.…”

“…However, a major challenge of such in vitro experiments is the translatability to patients. Recently, we have developed an integrative multiscale approach called PBPK-based in vivo contextualization of in vitro toxicity data (PICD) 14 that allows the translation of such in vitro findings to an in vivo context by coupling in vitro toxicity data with whole-body physiologically based pharmacokinetic (PBPK) models ( Figure 1).…”

A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

“…Whole-body PBPK models were initially established for a set of fifteen hepatotoxic drugs and were carefully validated with human experimental data from literature ( S3 Table ). The validated PBPK models served as input for PICD (PBPK-based in vivo contextualization of in vitro toxicity data) [ 20 ] to quantify in vivo drug responses induced by therapeutic and toxic doses administered in humans. Physicochemical properties, plasma protein binding, and lipophilicity of the different drugs and their metabolites were obtained from literature and were used to develop the reference PBPK model for intravenous administration in humans ( Table 1 ).…”

“…A severe drawback of such in vitro analyses, however, is often the limited translatability to the in vivo situation in patients in actual clinical practice. Recently, we have developed an integrative multiscale approach called PICD for the in vivo contextualization of in vitro toxicity data based on physiologically-based pharmacokinetic (PBPK) modeling, which significantly supports translations to an in vivo situation in patients ( Fig 1 ) [ 20 ]. Importantly, PBPK modeling aims for a mechanistic representation of absorption, distribution, metabolism, and elimination (ADME) processes governing drug pharmacokinetics (PK) within the human body.…”

Developing integrated PBPK/PD coupled mechanistic pathway model (miRNA-BDNF): An approach towards system toxicology

“…The calculated AUC was assumed to be equivalent with in-vivo AUC brain. Dose reconstruction approach has been used, so that the given equivalent oral dose will provide the AUC in the brain that matches the AUC for the 12 different in-vitro doses (6 for 24hr and 6 for 48hr), a similar approach has been used in the previous study (Thiel et al, 2017). The oral equivalent doses were estimated to be way higher, as the PFOS concentration reaching to the brain was found to be relatively very low (Fabrega et al, 2014;Fàbrega et al, 2016).…”