New concepts for personalized immunosuppression in the transplanted patient

Abstract

After transplantation patients receive individualized immunosuppressive treatment based on drug concentrations to hinder rejection of the transplant. This thesis aimed to develop and apply alternative methods of measuring the immunosuppressants tacrolimus, belatacept and mycophenolic acid. Tacrolimus exerts its effect inside lymphocytes but is measured in whole blood. An assay developed in this thesis showed that concentrations inside lymphocytes was only partially related to the whole blood concentration. It was also shown that the amount of tacrolimus that distributes to lymphocytes after dose may decrease during the first year after transplantation. A belatacept assay was developed and used to show that belatacept has a stable pharmacokinetic profile, but heavier patients may have a higher drug exposure since belatacept dose is adjusted according to body mass. The pharmacodynamic response of mycophenolic acid was measured in resting and ex vivo stimulated lymphocytes. Mycophenolic acid had a stronger effect on stimulated cells, but in a cohort of transplant patient both resting and stimulated cells appeared to become less sensitive during the first year after transplantation.