Individualization of immunosuppression: concepts and rationale.
OBJECTIVE
New immunosuppressive agents have decreased the incidence of acute rejection rates without improvement in long-term outcomes. Drug toxicity due to a narrow therapeutic index and individual variations in pharmacokinetics and pharmacodynamics significantly contributes to the inferior outcomes. This review focuses on advances in individualization of immunosuppression therapy using therapeutic drug monitoring and pharmacogenetics/pharmacogenomics as a strategy to minimize toxicity.


RESULTS
Although therapeutic drug monitoring for calcineurin inhibitors and mammalian targets of rapamycin inhibitors is well established, its utility in mycophenolate mofetil dosage adjustments is still the subject of ongoing debate. However, there is potential for optimizing mycophenolate mofetil therapy based on polymorphisms in genes that encode metabolizing and target enzymes. Single-nucleotide polymorphisms in cytochrome P450 genes have an effect on tacrolimus response. Donor genotype could have an effect on drug metabolism.


CONCLUSIONS
Therapeutic drug monitoring remains the most widely used method for individualizing immunotherapy. Improvements in molecular technology have enabled identification of several polymorphisms in genes that encode for drug-metabolizing enzymes, drug transporters, and their targets, which have an effect on individual response to therapy. Prospective studies are needed to explore this field and improve utility of donor and recipient genotype testing in managing immunosuppression therapy.
Wavamunno
Moses D
MD
Department of Renal Medicine and Transplantation, Westmead Hospital, Sydney, New South Wales, Australia.
Chapman
Jeremy R
JR
D000818:Animals; D065095:Calcineurin Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D005838:Genotype; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D016377:Organ Transplantation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D009173:Mycophenolic Acid