Prospects for personalized immunosuppression: pharmacologic tools--a review.
In the last few years, novel immunosuppressive agents and new formulations, including sirolimus, mycophenolic acid (the active metabolite of mycophenolate mofetil), tacrolimus, and microemulsion cyclosporine, have significantly improved the clinical outcome of transplant recipients. However, the majority of immunosuppressive agents need a constant monitoring of drug levels to reduce the risk of graft rejection as well as drug-induced toxicities. Many factors may affect the pharmacokinetic characteristics of immunosuppressive agents, potentially reducing treatment effectiveness. Absorption and metabolism of immunosuppressive drugs are influenced by patient genotype and comedications, while comorbidities (ie, diabetes and cystic fibrosis) are responsible for altered pharmacokinetics. Dose individualization in transplant recipients is performed according to their health status, graft function, and drug therapeutic range. With respect to the last issue, therapeutic drug monitoring (TDM) plays a crucial role in achieving optimal immunosuppression, improving the efficacy of drugs, and lowering toxic effects. Pharmacokinetic analysis allowed the identification of specific parameters, such as plasma or blood levels, immediately before dosing (C(min) or trough levels) or 2 hours after administration (C(2)), which are significantly related to tissue exposure to the drug. More recently, studies have investigated treatment individualization by evaluating drug pharmacogenetics based on the expression level or mutations of their molecular targets, including calcineurin for cyclosporine and tacrolimus, and inosine monophosphate dehydrogenase for mycophenolic acid. Although no conclusive data may be drawn from these preliminary trials, further studies are underway to address the role of pharmacogenetics in clinical decision making.
Del Tacca
M
M
Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy. m.deltacca@med.unipi.it
D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods* / Q000639:trends; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014181:Transplantation Immunology; D016896:Treatment Outcome
D007166:Immunosuppressive Agents