Clinical Pharmacogenetics in Pediatric Patients

Anwar Husain; Jennifer A. Loehle; David W. Hein

Disclosures

Pharmacogenomics. 2007;8(10):1403-1411. 

In This Article

Tranplantation

The human P-glycoprotein transporter gene (ABCB1), also known as the multidrug resistance 1 gene (MDR1), acts to expel many immunosuppressive drugs to the outside of the cell. Such drugs are often prescribed for patients having received transplant surgery as a means of suppressing the immune system to a degree necessary so that the body does not reject the newly implanted organ. Several key immunosuppressive drugs commonly used for this purpose that are substrates for the MDR1 transporter include cyclosporine, tacrolimus, sirolimus and corticosteroids. The MDR1 transporter may have a significant affect on the effectiveness and toxicity of drug therapy in transplant patients by altering intracellular drug concentrations. Many of the drugs are maintained throughout the life of the patient, although corticosteroids are most often removed from the drug regimen of individuals at increased risk for adverse affects from steroid treatment. Included in this population of at-risk patients are children, in whom corticosteroids have the potential to bring about growth suppression and other adverse affects. For this reason, many pediatric transplant patients are aggressively weaned off of steroid therapy.

Approximately 16 different SNPs have been identified within MDR1.[6,7,8,9,10] Zheng et al. looked at the C3435T noncoding SNP at exon 26 and the G2677T missense SNP at exon 21 haplotype in relation to the weaning of steroids in a population of pediatric patients who had been treated with tacrolimus and prednisone-based immunosuppressive therapy from the time of heart transplantation.[11] Attempts to wean patients from corticosteroid therapy were made within 1 year of surgery, dependent upon results of surveillance endomyocardial biopsies. The ultimate goal of therapy was to initiate those patients with no history of early rejection on monotherapy with tacrolimus, and manage those patients experiencing recurrent early rejection with long-term, steroid-free dual therapy when and as soon as possible. At 1 year after heart transplant surgery, in regards to the MDR1 C3435T SNP, 67% of patients with the CC genotype were still receiving steroid therapy, whereas only 38% of the patients with the CT/TT genotype were still receiving prednisone. Similarly, for MDR1 G2677T, 65% of patients possessing the GG genotype were still receiving steroid therapy, versus only 40% of the GT/TT group. The conclusion is drawn that a significantly larger number of heart transplant patients with the MDR1 3435 CC genotype remain on steroids 1 year after surgery. Of patients with the MDR1 3435 CC genotype, 94% were also of the MDR1 2677 GG genotype, and of the patients possessing a C3435T allele, 93.5% also possessed a G2677T allele. These results suggest that patients with the MDR1 3435 CC genotype and the 2677 GG genotype require more aggressive alternative treatment regimes when being weaned from corticosteroid immunosuppressive therapy. These SNPs may serve as MDR1 genotype markers that could give clinicians a means of predicting which pediatric transplant patients may be weaned sooner from immunosuppressive steroid therapy and which patients require more aggressive immunosuppressive therapy when being weaned from steroids. Specific MDR1 genotypes required larger doses to maintain their tacrolimus blood concentration.[11]

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