Alterations in immunosuppression in heart transplant patients

Significant improvement in surgical techniques of heart transplantation, intensive care and immunosuppression have increased the graft and recipient survival in recent decades; however, particular attention should be paid to the patients’ genetic and non-genetic variations in drug metabolism and to pharmacokinetic drug-interactions between immunosuppressants and post-transplant medication which require personalized pharmacotherapy both in early and in late post-transplantation periods. The project focuses on the key CYP3A enzymes involved in the metabolism of most immunosuppressants (calcineurin inhibitors, mTOR inhibitors, corticosteroids), because genetic polymorphisms and phenoconversion of CYP3A enzymes affect the blood concentrations of immunosuppressants. Low or extensive drug-metabolizing capacity producing excessive or sub-therapeutic drug concentrations has the potential risk for adverse reactions or the lack of therapeutic effect. Revealing the regulatory role of corticosteroids in the expression of CYP3A enzymes and nuclear receptors can contribute to understanding the fluctuation of drug-metabolizing capacity as a consequence of switch from tacrolimus-mycophenolate-corticosteroid combination therapy to steroid-free therapy. Continuous monitoring of recipients’ CYP3A-status will provide a pharmacokinetic tool for dynamic optimization of immunosuppressive therapy, whereas NFAT-regulated cytokine production as a response to changes in immunosuppressive therapy or to any clinical factors (transient co-medication, changes in physiological state, disease) may serve as a sensitive pharmacodynamic marker for optimization of immunosuppression. Biochemical, clinical manifestations (graft function, complications) and hospitalization data may demonstrate the benefit of CYP3A-status and cytokine production controlled, dynamically optimized immunosuppressive therapy. Tailored medication will lead to the optimization of drug choice and/or dosage for a more effective therapy, and may facilitate reduction of serious adverse effects and improvement of graft and recipient survival.

Katalin Monostory - Balázs Sax