Current progress in pharmacogenetics and individualized immunosuppressive drug dosing in organ transplantation.
The immunosuppressive drugs used in organ transplantation typically have a narrow therapeutic index, with wide variation in the blood concentration achieved from a given dose observed between individuals. This issue has been addressed through the use of therapeutic drug monitoring (TDM), but it may take 5 to 7 days to reach target blood concentrations using this approach. This timeline is not conducive to achieving sufficiently high concentrations in all patients to prevent graft rejection without exposing the patient to excessive toxicity over the critical 2- to 3-day period following transplantation. SNPs in drug-metabolizing enzymes and transporter proteins have been associated with the pharmacokinetic and pharmacodynamic characteristics of immunosuppressive drugs. Data suggest that genetic prediction of the optimal initial drug dose leads to earlier attainment of target blood concentrations compared with using the standard initial dose. The pharmacogenetic strategy that is closest to translation into clinical practice is the use of the cytochrome P450 (CYP)3A5 genotype to predict the optimal initial dose for tacrolimus. Genetic prediction of the optimal dose may be particularly useful for drugs with a long half-life, such as sirolimus, which require several days to achieve a steady state following the implementation of a change in drug dosing, resulting in a long response-time for TDM. The influence of genetic factors on intracellular drug concentrations and the consequences for efficacy and toxicity are an emerging area of research. The SNPs described in this process could be added to existing molecular tissue typing methodology at minimal extra financial expense.
Ware
Nicholas
N
University of London, St George's Hospital, Cranmer Terrace, London, SW17 0RE, UK.
MacPhee
Iain A M
IA
D051544:Cytochrome P-450 CYP3A; D016903:Drug Monitoring; D005838:Genotype; D006084:Graft Rejection / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D010597:Pharmacogenetics / Q000379:methods*; D020123:Sirolimus; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus; D016559:Tacrolimus