Cellular metabolism continuously processes an enormous range of external compounds into endogenous metabolites and is as such a key element in human physiology. The multifaceted physiological role of the metabolic network fulfilling the catalytic conversions can only be fully understood from a whole-body perspective where the causal interplay of the metabolic states of individual cells, the surrounding tissue and the whole organism are simultaneously considered. We here present an approach relying on dynamic flux balance analysis that allows the integration of metabolic networks at the cellular scale into standardized physiologically-based pharmacokinetic models at the whole-body level. To evaluate our approach we integrated a genome-scale network reconstruction of a human hepatocyte into the liver tissue of a physiologically-based pharmacokinetic model of a human adult. The resulting multiscale model was used to investigate hyperuricemia therapy, ammonia detoxification and paracetamol-induced toxication at a systems level. The specific models simultaneously integrate multiple layers of biological organization and offer mechanistic insights into pathology and medication. The approach presented may in future support a mechanistic understanding in diagnostics and drug development. Cellular metabolism is a key element in human physiology. Ideally the metabolic network needs to be considered within the context of the surrounding tissue and organism since the various levels of biological organization are mutually influencing each other. To mechanistically describe the interplay between intracellular space and extracellular environment, we here integrate the genome-scale metabolic network model HepatoNet1 at the cellular scale into physiologically-based pharmacokinetic models at the whole-body level. The resulting multiscale model allows the quantitative description of metabolic behavior in the context of time-resolved metabolite concentration profiles in the body and the surrounding liver tissue. The model has been applied to three case studies covering fundamental aspects of medicine and pharmacology: drug administration, biomarker identification and drug-induced toxication. Most notably, our multiscale approach fosters an improved quantitative understanding of drug action and the impact of metabolic disorders at an organism level, based on a genome-scale representation of cellular metabolism. Computational models such as the one presented include various aspects of human physiology and may therefore significantly support rational approaches in medical diagnostics and pharmaceutical drug development in the future.

Models of glucose metabolism are a valuable tool for fundamental and applied medical research in diabetes. Use cases range from pharmaceutical target selection to automatic blood glucose control. Standard compartmental models represent little biological detail, which hampers the integration of multiscale data and confines predictive capabilities. We developed a detailed, generic physiologically based whole‐body model of the glucose‐insulin‐glucagon regulatory system, reflecting detailed physiological properties of healthy populations and type 1 diabetes individuals expressed in the respective parameterizations. The model features a detailed representation of absorption models for oral glucose, subcutaneous insulin and glucagon, and an insulin receptor model relating pharmacokinetic properties to pharmacodynamic effects. Model development and validation is based on literature data. The quality of predictions is high and captures relevant observed inter‐ and intra‐individual variability. In the generic form, the model can be applied to the development and validation of novel diabetes treatment strategies.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e65; doi:10.1038/psp.2013.40; published online 14 August 2013

Goal: Automated glucose control (AGC) has not yet reached the point where it can be applied clinically [3]. Challenges are accuracy of subcutaneous (SC) glucose sensors, physiological lag times, and both inter- and intraindividual variability. To address above issues, we developed a novel scheme for MPC that can be applied to AGC. Results: An individualizable generic whole-body physiology-based pharmacokinetic and dynamics (PBPK/PD) model of the glucose, insulin, and glucagon metabolism has been used as the predictive kernel. The high level of mechanistic detail represented by the model takes full advantage of the potential of MPC and may make long-term prediction possible as it captures at least some relevant sources of variability [4]. Robustness against uncertainties was increased by a control cascade relying on proportional-integrative derivative-based offset control. The performance of this AGC scheme was evaluated in silico and retrospectively using data from clinical trials. This analysis revealed that our approach handles sensor noise with a MARD of 10%-14%, and model uncertainties and disturbances. Conclusion: The results suggest that PBPK/PD models are well suited for MPC in a glucose control setting, and that their predictive power in combination with the integrated database-driven (a priori individualizable) model framework will help overcome current challenges in the development of AGC systems. Significance: This study provides a new, generic, and robust mechanistic approach to AGC using a PBPK platform with extensive a priori (database) knowledge for individualization.

Physiologically-based kinetic (PBK) models are effective tools for designing toxicological studies and conducting extrapolations to inform hazard characterization in risk assessment by filling data gaps and defining safe levels of chemicals. In the present work, a generic avian PBK model for male and female birds was developed using PK-Sim and MoBi from the Open Systems Pharmacology Suite (OSPS). The PBK model includes an ovulation model (egg development) to predict concentrations of chemicals in eggs from dietary exposure. The model was parametrized for chicken (Gallus gallus), bobwhite quail (Colinus virginianus) and mallard duck (Anas platyrhynchos) and was tested with nine chemicals for which in vivo studies were available. Time-concentration profiles of chemicals reaching tissues and egg compartment were simulated and compared to in vivo data. The overall accuracy of the PBK model predictions across the analyzed chemicals was good. Model simulations were found to be in the range of 22-79% within a 3-fold and 41-89% were within 10- fold deviation of the in vivo observed data. However, for some compounds scarcity of in-vivo data and inconsistencies between published studies allowed only a limited goodness of fit evaluation. The generic avian PBK model was developed following a "best practice" workflow describing how to build a PBK model for novel species. The credibility and reproducibility of the avian PBK models were scored by evaluation according to the available guidance documents from WHO (2010), and OECD (2021), to increase applicability, confidence and acceptance of these in silico models in chemical risk assessment.

An extensive battery of 17 in vitro assays has been developed for assessing developmental neurotoxicity (DNT), with the aim of replacing or supplementing traditional in vivo guideline studies for risk assessment, as these mechanistic assays provide advantages over costly, lengthy in vivo studies. However, 1 major challenge in employing in vitro assays is the translation of in vitro bioactive concentrations into in vivo doses that can be compared with human exposures. This study describes an in vitro to in vivo extrapolation (IVIVE) approach to derive human-relevant administered equivalent doses based on chemical partitioning into DNT target organs during the critical period of brain development. We used data from chemicals previously found to elicit bioactivity in a subset (7 of 17) of the in vitro DNT battery assays conducted at the US Environmental Protection Agency. Three physiologically based pharmacokinetic modeling platforms were evaluated for their suitability for this DNT-IVIVE approach. Chemical predictions for administered equivalent doses were compared against in vivo effect levels, where available, and found to be within 3-fold for 78% of chemicals. To provide metrics for risk assessment considerations, administered equivalent doses were compared with predicted human exposures. Overall, this DNT-IVIVE approach was found to be relatively transferable among modeling platforms, albeit with varying limitations and considerations that should be taken into account for specific contexts of use.