Validation and Optimization of In Vitro Hepatocyte Systems and Physiologically Based Pharmacokinetic Modelling for Translation of Drug Metabolism to Human

In the last few decades, great strides were made in predicting pharmacokinetic drug properties to reduce attrition rates of drug projects in the clinical phase due to unfavorable pharmacokinetic characteristics. Nonetheless, capability gaps still remained and emerged during the past years. Optimization of the metabolic stability of drugs to avoid metabolism by the cytochrome P450 enzymes led to increasing relevance of alternative drug metabolizing enzymes and routes of clearances. On a related note, the importance of UDP-glucuronosyltransferases as metabolizing enzymes for new chemical entities increased, which formed the challenge of determining and translating the metabolism of a less well-established enzyme family. Furthermore, novel in silico and in vitro test systems are constantly adopted in the pharmaceutical industry with the promise to improve the quality of the pre-clinical data, whereas the systems must be fundamentally evaluated and assessed before routine application during the drug development.
The aims of the PhD project was to address current capability gaps to enhance the confidence in the prediction of human clearance and to evaluate a novel in vitro hepatocyte system. We investigated the translatability of UGT-mediated drug clearance by using a promising hepatocyte co-culture and physiologically based pharmacokinetic modelling and simulation. In addition, we aimed to advance the adoption of novel in vitro hepatocyte system that potentially offers new capabilities of determining more complex research questions during the drug development. These studies resulted in three published manuscript and in one on-going work that is planned to be finalized and submitted in the near future:
1. In Vitro to In Vivo Extrapolation of Metabolic Clearance for UGT Substrates Using Short-Term Suspension and Long-Term Co-Cultured Human Hepatocytes
2. Construction and Verification of Physiologically Based Pharmacokinetic Models for Four Drugs Majorly Cleared by Glucuronidation: Lorazepam, Oxazepam, Naloxone, and Zidovudine
3. Application of New Cellular and Microphysiological Systems to Drug Metabolism Optimization and Their Positioning Respective to In Silico Tools
4. Optimization of a Liver-on-Chip System for DMPK Application and Combination with Modelling and Simulation
We demonstrated for the first time that an improvement is achieved upon the application of a hepatocyte co-culture for the in vitro to in vivo extrapolation of metabolic clearance. We could further identify and discuss current limitations for physiologically based pharmacokinetic modelling and simulation based on well-constructed models. With the review, we reported the state of the art for the application of conventional and more advanced hepatocyte systems as parts of the value chain during drug development in relation to computational approaches. Finally, we evaluated a microphysiological system (i.e. liver-on-chip device) for the application of DMPK determination. Overall, the studies have a positive impact on the decision-making process during the pre-clinical drug development and increase the confidence in the application of the hepatocyte co-culture and PBPK modelling for UGT substrates.
To the structure of the thesis: The introduction will familiarize the reader to the elements that were key to the PhD program: metabolic clearance and factors affecting the drug metabolizing enzymes, in vitro hepatocyte systems for the determination of DMPK properties, and physiologically based pharmacokinetic modelling (i.e. computational approaches) and its relevance in the pharmaceutical industry. The introduction will further highlight the current gaps and limitations that exist in the field and elaborates on the outline and plans of the studies conducted during the project. The results section contains the manuscripts that report the core studies conducted in the past three years. Finally, the “Summary and Future Investigations” section papers summarizes the work with an emphasis on the impact of the studies for the pharmaceutical industry and complements the thesis with next investigations that should be conducted in order to extend the work.