Active substances of drugs, alone or in combination with each other, herbs and herbal supplements are metabolized by the human liver. This metabolization can be associated with irreversible damage or even death of the patient. There is no effective prevention against this problem. Additionally, there is no simple drug testing preclinical system to decipher hepatotoxicity issues undoubtfully at early stages of the drug development. Deeper understanding of drug-induced liver injury (DILI) mechanisms is the goal of an international team of experts from the Prospective European Drug-induced Liver Injury Network (PRO-EURO DILI Network), who met on March 9 and 10 at the Institute of Physics of the Academy of Sciences of the Czech Republic.
They shared their experience and findings from the first stage of joint research on DILI and set plans for the future development of cooperation among different disciplines to mitigate the DILI problem. The PRO-EURO DILI Network will expand the DILI issue towards not only standard drugs but also to herbs and herbal supplements. It becomes evident that herbs and herbal supplements can cause liver damage, either when used incorrectly or in combination with certain medications.
"The main goal of the first phase of the joint investigation of drug-induced liver damage was the creation of a pan-European network that would proceed in a coordinated and mutually agreed manner. It is important not only to investigate the causes of this disease and its appropriate prevention, but also to spread awareness about it, and the PRO-EURO DILI Network consortium succeeded in this," said Alexandr Dejneka, Head of the Division of Optics, whose scientists are involved in the network.
One of the aims of the next phase of this joint research is the prevention of the so-called idiosyncratic DILI, i.e., a rare condition occurring independently of a drug dose, or route or duration, of administration. The next phase of the research will therefore be examining and scaling samples of damaged liver so that it were possible to determine in advance who who is at risk of suffering from DILI when administered a particular drug.
Another path of the upcoming research is the creation of a liver-on-chip system (potentially created utilizing different cell types present in human liver) simulating functions of the liver. The last stage of this research direction is to create a 3D model of the human liver as a basis for drug testing.
"The goal of the working group, which our team from FZU takes part in, was to review the current expertise on preclinical methods and technologies that assess the risk of DILI based on the action of a given drug, and thereby contribute to better regulatory decision-making regarding DILI. In the future, we would like to contribute to the creation of a realistic and regulatory authority-approved liver model on which possible drug toxicity could be investigated," said Oleg Lunov, head of the Laboratory of Biophysics, where drug-induced liver damage is researched at FZU.
Within the PRO-EURO DILI Network there are five working groups dealing, for example, with the standardization of approaches to the diagnosis of drug-induced liver damage, the assessment of the hepatotoxicity potential of individual drugs and their interaction or trying to contribute to better decision-making by regulatory bodies related to DILI. Their goal is also to establish standards for clinical trial designs and precise criteria for evaluating the effectiveness of new interventions or for investigating new biomarkers in DILI. They also want individual data from clinical trials of drugs in development to be shared even after they are on the market in case DILI has been identified. And finally, the goal is to spread awareness about DILI both among healthcare professionals and the general public.
Investigating DILI and understanding it begins with a drug's preclinical development, through clinical trials, to its launch on the market. The goal of the PRO-EURO-DILI-NET Cost Action is to create a unique, cooperative, interdisciplinary European DILI network that would coordinate efforts of experts from different research fields in understanding mechanisms of DILI development. The network connects several hundred experts from 28 countries around the world.