Orion Corporation [HEL: ORNBV]

Drug Metabolism and Pharmacokinetics (DMPK) plays a critical role in drug development by helping to ensure the safety and efficacy of new drugs. DMPK is a multidisciplinary branch of science that studies the behavior of drug candidates in the body, including their absorption, distribution, metabolism, and elimination. In a drug discovery process, DMPK information helps identify the most promising drug candidates, optimize their formulation and dosing regimen. This information is critical for the design and execution of preclinical and clinical trials, and the eventual approval of new drugs by regulatory agencies. The goal of a drug discovery process is to find a drug that is both safe and effective. Safety is assessed by determining the exposure levels of the drug causing adverse events, while efficacy is evaluated by determining the minimum effective exposure. To achieve this, scientists must understand the dose-exposure-response relationship of a particular drug. The information is used to guide the development of the drug from early discovery to clinical trials.

Dose-exposure-response is a critical concept in drug discovery as it describes the relationship between the amount of drug administered, the level of the drug in the body (exposure), and the resulting biological response (effect). In simple terms, it explains how a drug works in the body and how the dose and exposure level impact the therapeutic effect. The dose-exposure-response relationship is influenced by many factors, including pharmacokinetics (PK), pharmacodynamics (PD), and safety. PK describes how the drug is absorbed, distributed, metabolized, and eliminated from the body. PD defines how the drug works in its target. Therefore, target protein, the mechanism of action, and the downstream signaling pathways are all important aspects of PD that have an impact on the dose-exposure-response relationship. In the early stages, safety is assessed by determining the adverse events of the drug in animals that are in-vivo models. This helps to identify potential toxicity alerts before the drug is tested in humans. 

Although researchers use multiple models involving in-silico models, in-vitro and  in-vivo tools to characterize the complex dose-exposure-response relationship in early drug discovery, there is an urgent need for better performing models in terms of speed and better prediction. Organ-on-chip (OOC) tools are interesting new technologies to understand this better and guide the DMPK & safety in early drug discovery.

“Although researchers use multiple models involving in-silico models, in-vitro and  in-vivo tools to characterize the complex dose-exposure-response relationship in early drug discovery, there is an urgent need for better performing models in terms of speed and better prediction.”

OOC models involve microfluidic devices that mimic the function of human organs. OOC models contain living cells that are cultured in a controlled environment to assess the toxicity and efficacy of drugs, also allowing the study of DMPK processes such as drug metabolism and transport. These models enable the control of the cell environment, such as mimicking the flow of blood. The use of OOC in drug discovery promises to provide various advantages over traditional in-vitro methods, including 2D cell-based assays or animal in vivo studies. For instance, to study metabolic processes in a more patient- relevant manner. They also explore multi-organ interaction of drugs, like the liver and the gut, in a controlled and reproducible manner. In addition, OOC is expected to reduce the use of animal studies in drug discovery.  Organ-on-chip technology is an exciting and rapidly evolving field that has the potential to remarkably speed up the process, increase the confidence of preclinical models, and reduce costs in safety and efficacy testing of drugs and chemicals.

Like any other novel technology, OOC is also associated with a few limitations. One of the challenges is scalability in terms of throughput of models. The current applications are still focused on a few specific organs.  The bulk experience for multiple chemical compounds and biological effects is also still evolving, which may be a challenge for the regulatory agencies. The domain expects continued efforts from biology, engineering, and data science sectors.

In summary, understanding DMPK and safety is extremely important in drug discovery. With an understanding of the relationship, dose-exposure-response can be more reliably assessed, leading to a more efficient discovery process. Therefore, there is an urgent need for developing new methods and tools, where one of the most promising developments  is Organ-On-Chip technology.