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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Optimization of drug therapy based on considerations of host-microbiome interplay

Alternative title: Optimalisering av legemiddelbehandling basert på kunnskap om tarmmikrobiomets effekt på legemiddelomsetning i pasienter

Awarded: NOK 8.0 mill.

It is becoming increasingly clear that gut bacteria influence drug disposition. In this project we will investigate if different composition of gut microbiota can explain the large variation in drug response observed between patients and how this will affect dosing of drugs. Differences in drug response between patients are a common and well-known challenge in clinical practice. The same dose of a drug can be effective and safe in one patient and give rise to side effects or therapeutic failure in another. This difference is partly due to different expression and activity of drug metabolizing enzymes located in the intestine and liver which are key determinants of drug disposition. Despite our current knowledge of how drug metabolizing enzymes, disease, genetics and environmental factors contribute to variability in drug response, there is still a large part that is unexplained. It is becoming increasingly clear that the community of microorganism that are full-time residents in our gut may influence drugs, either directly by direct degradation in the gut or indirectly by influencing the activity of drug metabolizing enzymes. However, we currently lack detailed understanding of the gut microbiota?s contribution to drug metabolism and the effect on drug dosing. In this project, we will analyze serial feces samples (collected over a 2-year period) from 100 patients included in a large clinical trial. We also have detailed data of systemic exposure of selected drugs, and expression and activity of drug metabolizing enzymes in the liver and intestine. We will investigate both the direct contribution of gut bacteria on drug metabolism and the impact of the individual gut microbiota profile on drug metabolizing enzymes and drug exposure. Advanced mathematical models will be used to integrate data and study the host-drug-gut microbiota interplay. The project will, if successful, provide an important step in the progress towards even more precise personalized medicine.

Drug treatment is the most common therapeutic intervention. However, there is large interindividual variability in drug response, affecting both efficacy and toxicity. As drug metabolism and transport are important determinants of drug disposition and response, extensive knowledge of factors contributing to the variability in these processes are required in order to individualize drug therapy. Emerging evidence implies an extensive role of gut microbiota in determining the systemic exposure of drugs. However, despite their important consequences for human biology, the gut microbes' involvement in drug metabolism and transport is poorly understood and data from human subjects are lacking. In this project, we will utilize samples and data from a large clinical trial designed to shed light on the impact of gut microbiota composition on key drug metabolizing enzymes and transporters. The material includes serial feces samples (collected during a 2-year period) and detailed pharmacokinetic data from over 100 patients; systemic exposure of selected clinical probe drugs in vivo and protein expression and ex vivo activity of drug metabolizing enzymes and transporters in paired liver and intestinal biopsies. As feces samples are obtained at the same time point as the pharmacokinetic investigations, the gut microbiome will be analyzed (whole genome sequencing) and the impact of the individual gut microbiota profile on drug metabolism and transport in vitro and in vivo will be assessed. Also, we will study whether individual changes in gut microbiota composition over time can predict alterations in the systemic exposure of the probe drugs. Finally, physiologically-based pharmacokinetic modelling will be used to integrate the in vitro and clinical data, enabling an unprecedented level of mechanistic understanding of the host-microbiome-drug interplay. This will, if successful, provide a breakthrough in the progress towards personalized medicine and individualized healthcare.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

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