Short Course Program
This meeting will offer attendees an opportunity to register separately for up to two short courses. One short course will be held in the morning, followed by a complimentary lunch for course attendees and the two concurrent afternoon short courses. Short courses may be added to any new or existing meeting registration.
Register for two short courses and save 25% on your short course registration!
Short Course 1: Primary human hepatocytes: basic aspects
Primary human hepatocytes (PHH) exhibit unique complexity and diverse functions: they contain a broad complement of metabolizing enzymes and transport proteins organized in a physiologically relevant context. The function of PHH strongly affects pharmacokinetics, side effects and toxicity of drugs. In this course the basic aspects of PHH use and function, and what they can offer in R&D is explained. The course will thus cover topics such as handling of hepatocyte cultures and their use for prediction of drug metabolism, transport and toxicity, different systems for long term cultivation with regard to predict clearance and metabolite formation as well as an introduction to quantitative in vitro-in vivo modeling.
1. Hepatocytes - what they can do in ADME research (intro of usefulness)
2. Metabolism & induction studies
3. Clearance & transporter studies
4. Toxicity studies
5. Long term culture of pHH
6. Modeling in ADME
Short Course 2: Advanced culturing of human hepatocytes
Cultures of primary human hepatocytes (PHH) are routinely used in drug development to evaluate metabolic fate, drug-drug interactions and drug toxicity. The supply of PHH is however limited and the longevity of PHH cultures is short due to the rapid de-differentiation of hepatocytes in 2D cultures causing a change of cell function including low expression of ADME genes. In this session, new approaches are presented that elongate the lifespan of PHH and mimic in vivo like functions and possibilities for studying liver diseases, chronic drug toxicity, time dependent enzyme inhibition and long term drug metabolism in vitro. The systems include organs on a chip models, microengineered liver perfused platforms, bioprinted 3D liver tissues and 3D liver spheroids.
2. Microfabricated liver models
3. 3D Printing
4. 3D Spheroids
5. Liver on a chip
Short Course 3: Quantifying the in vivo Activity of Human Drug Metabolizing Enzymes and Transporters
The activities of individual human drug metabolizing enzymes and transmembrane transporter proteins often represent the ‘bottlenecks’ determining key pharmacokinetic properties of small molecule drugs and other xenobiotics. While these activities can be quantified in vitro, the complexity of the human body as well as various sources of variability prevent direct transfer to the complete organism. Accurate quantification of enzymes and transporters activities in vivo (phenotyping) is therefore essential to predict the pharmacokinetics of respective substrates as well as the effect of an intervention (e.g., drug therapy, diet) or a condition (e.g., genetic polymorphism, disease) thereon. Phenotyping is typically done by administration of a selective substrate of the respective enzyme/transporter and subsequent assessment of suitable pharmacokinetic parameters (‘metrics’, e.g., hepatic clearance or renal secretion) reflecting their (local) activity. While this involves the withdrawal and processing of numerous blood and/or urine samples, respective approaches are well-established for the relevant cytochrome P450 enzymes in healthy volunteers. Such methods are currently also being tested for the assessment of transporter activities, where the interplay between uptake and efflux transporters even in the same cells as well as the promiscuity of substrate / transporter interactions are major challenges.
The need for administration of test substances may be overcome by using metrics derived from concentrations of endogenous substrates. Although this approach is not new, improvements in understanding of the fate of such substances as well as metabolomic and genome-wide association methods may become the basis for its broader application. Other approaches aimed at improving the cost/benefit ratio of phenotyping include combination of probe drugs in cocktails and/ or reducing the expense of sampling and sample processing.
The phenotyping approach is mainly accepted and applied to identify and quantify the potential of novel drugs to cause drug-drug interactions. Caveats apply for the direct transfer of respective data to patient groups where pharmacokinetic bottlenecks other than those relevant in healthy volunteers may be relevant.
1. Actual phenotyping methods including their validation and limitations
2. Efforts to find new phenotyping metrics
3. Practical aspects of generating respective data in an economically advantageous way
4. Examples for results of respective clinical trials and their use for drug labeling.