Orion Corporation

Antti Haapalinna

Drug Metabolism and Pharmacokinetics (DMPK) plays a critical role in the 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 the drug discovery process, DMPK information helps to identify the most promising drug candidates and to optimize their formulation and dosing regimen. This information is critical for the design and execution of preclinical and clinical trials, as well as for the eventual approval of new drugs by regulatory agencies. In drug discovery, the goal 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 for a particular drug. This 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 several factors, including the pharmacokinetics (PK), thepharmacodynamics (PD) and the safety. PK describe how the drug is absorbed, distributed, metabolized, and eliminated from the body. The 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 the dose-exposure-response relationship. In the early stages the safety is assessed by determining the adverse events of the drug in animal in vivo models. This helps to identify potential toxicity alerts before the drug is tested in humans.

"Organ-on-chip technology is an exciting and rapidly evolving field that has the potential to remarkable to speed up, increase the confidence of preclinical models and reduce costs in safety and efficacy testing of drugs and chemicals"

In early drug discovery, researchers use multiple models involving in silico, in vitro and to in vivo tools to characterize the complex dose-exposure-response relationship, and there is an urgent need for better performing models in terms of speed and better human prediction. Organ-on-chip (OOC) tools are interesting new technologies to understand better and guide the DMPK&Safety in early drug discovery. OCC models involve microfluidic devices that mimic the function of human organs. OOCs contain living cells that are cultured in a controlled environment to assess the toxicity and efficacy of drugs, but also allow to study 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 has a promise to provide several advantages over traditional in vitro methods, including 2D cell-based assays or animal in vivo studies, e.g. to study of metabolic processes in a more patient relevant manner. They also allow for the 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 remarkable to speed up, increase the confidence of preclinical models and reduce costs in safety and efficacy testing of drugs and chemicals.

As with all novel technologies there are still several limitations with the OOC. One of the challenges is the scalability in terms of through-put of the models; the current applications are still somewhat focused in specific questions in particular organs. Furthermore, the bulk experience for multiple chemical compound and biological effects is still evolving, which may be a challenge for the regulatory agencies. Continuing efforts are expected regarding expertise from the biology, engineering, and the data science.

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