Influence of gut microbiome on drug dosing
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 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.
CYP3A-activity in different patient populations
Most drugs are metabolized by enzymes in the intestine and liver. These enzymes are called drug-metabolizing enzymes, and one of the most important of these enzymes is called CYP3A. By using a so called probe drug, the activity of CYP3A can be determined. This is of interest, for example during drug development, in drug-drug interaction studies or drug dosing studies. Midazolam is the most commonly used probe to study CYP3A-activity, and is considered the "gold standard". We have several projects where we use midazolam as a probe drug to study CYP3A-activity in different patient populations (patients with obesity/critically ill children/patients with systemic sclerosis/patients with chronic renal failure/healthy volunteers).
Individualized dosing of immunosuppressive drugs
Solid organ transplant recipients are dependent on life-long immunosuppressive treatment to prevent rejection of the new organ. The immunosuppressive protocol after kidney transplantation currently consists of a combination therapy with a calcineurin inhibitor, mostly tacrolimus or occasionally cyclosporine, mycophenolate and steroids. Both tacrolimus and cyclosporine have a narrow therapeutic window and many side effects. Therapeutic drug monitoring is mandatory for this patient population to ensure a sufficient effect while limiting side effects. However, it can be challenging to dose correctly due to a narrow therapeutic window and low correlation between dose and blood concentration due to large intra- and inter-individual pharmacokinetic variability.
Drug Metabolism (in vitro)
Studies of drug metabolism by using microsomes is the longest used method within the PK-group. We work both with human liver microsomes that express all enzymes found in a normal liver and microsomes that only express certain CYP enzymes. In addition, we create individual intestinal and liver microsomes from biopsies from patients. With the help of these methods, we can investigate which enzymes metabolize various drugs and which other substances possibly inhibit these processes.
In the above-mentioned projects, we also use of pharmacokinetic population modeling in order to improve our understanding and to estimate variability in the pharmacokinetics of the various drugs. Population pharmacokinetic dosing models utilize relationships between patients' physiological and genetic characteristics, pharmacokinetic variation in the population and measured drug concentrations to predict individual dosing requirements. Pharmacokinetic population models can also be used to determine optimal sampling times in traditional clinical pharmacokinetic studies and thus save both time and costs. In addition, we also use physiology-based pharmacokinetic modeling to make in vitro-in vivo extrapolations.