title: The impact of genetic polymorphisms on time required to attain the target tacrolimus levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients.
abstract: Recent pharmacogenetic studies involving various transplant recipients in diverse ethnic populations revealed contradictory findings regarding the impact of CYP3A5 and multidrug resistance-1 (MDR1) single nucleotide polymorphisms (SNPs) on the pharmacodynamics of tacrolmius (TAC). The aim of the current study was to evaluate the impact of these SNPs on the time required to attain target TAC levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013, and MDR1 C3435T. Notably, none of the patients expressing CYP3A5 FNx011FNx011 or FNx011FNx013 achieved the target concentration of 10-20 ng/mL within the first 2 weeks or even the first month after transplant. However, 34.4% of CYP3A5 FNx013FNx013 achieved and maintained the target goal within the first and second weeks (P <0.05). In contrast, C3435T polymorphism had no significant influence on the proportion of patients achieving target TAC levels. An examination of the impact of genotype combinations on clinical outcomes revealed an increased incidence of acute, chronic rejection and graft loss in patients carrying heterozygous MDR1 C3435T alleles (CT); this indicates the possibility of an additive effect of this SNP on its concurrent combination with a FNx013FNx013 SNP. In conclusion, our study revealed trends toward unwanted outcomes in CYP3A5 non-expressers with an unexplained correlation with MDR1 C3435T polymorphisms. Recommending routine pharmacogenetic testing of the individual SNPs in renal transplant patients is not yet feasible as the relationship of cost-effectiveness to ultimate impact on graft or patient survival must be justified by further prospective clinical trials.
authors.affiliation: Department of Clinical Pharmacy Practice, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
authors.forename: Sireen
authors.initials: S
authors.lastname: Shilbayeh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood / Q000235:genetics; D000293:Adolescent; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000097:blood / Q000235:genetics; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus