Individualized Drug Therapy -- Treatment selection and dose optimization based on individual patient characteristics

The primary aim of the project is to investigate the influence of drug transporters on the pharmacokinetics, and the effect, of immunosuppressive drugs. This knowledge is hopefully possible to implement in sophisticated models in order to give a better prediction of the effect of different doses in transplanted patients. So far in this project we have developed an analytical method to measure steroids and investigated their pharmacokinetics in transplanted patients. Steroids are substances that can alter drug transporter expression and activity. In addition we have analyzed the protein expression drug uptake transporters in human liver tissue and seen that this transporter influences the levels of a lipid-lowering drug (atorvastatin). In conjunction to this study we have also developed in vitro models, including using stem cells, which can be used to investigate this specific transport in the lab. The laboratory data on the function of this transporter in vitro has been used in an in vitro-in vivo extrapolation analysis to use a computer to predict the effect of this transporter on atorvastatin levels in humans. These data has also been used to develop a population model for the immunosuppressive drug tacrolimus. This model has been tested against experienced transplant physicians and how they managed to dose tacrolimus in renal transplant recipients. The computer model dosed tacrolimus better than the physicians. We have also been able to measure the activity of an efflux transporter (P-gp) in T-cells and looked at the association with blood and T-cell concentrations of the immunosuppressive drug everolimus.

The focus on molecular biology to explain interindividual variability in drug pharmacokinetics and pharmacodynamics has increased in recent years. This is not only of importance during new drug development, but also for therapy optimalization of already m arketed drugs. With respect to pharmacokinetics, there is considerable knowledge about drug metabolising enzymes. However, the role of drug transporter proteins for the uptake, intracellular accumulation and efflux of drug compounds in different organs is incompletely understood. Current pharmacokinetic models and applications of TDM do not take these transporters into consideration, and therefore the full potential of these models to predict local concentrations of drugs and hence clinical efficacy and s afety are not fully exploited. The aim of the present project is to increase our knowledge on drug transporters, and specifically to integrate this within a concept that also includes drug metabolism. This fits well within both the clinical pharmacy as we ll as the safety pharmacology headings of ISP-FARM. The project is an integrated part of the overall research of the PK-group with clearly defined boundaries and supervision responsibility. International cooperation is already established with several gro ups that are involved in this kind of research at a high level. It is believed that this project will add basal knowledge to mechanisms important to predict drug concentrations in clinical settings and in this way improve individualized drug dosing.