CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients

Pharmacogenomics. 2013 Jul;14(9):1027-36. doi: 10.2217/pgs.13.80.

Abstract

Background: Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients.

Methods: Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers.

Results: CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001).

Conclusion: Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • Cytochrome P-450 CYP3A / genetics*
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression / genetics
  • Genotype*
  • Heart Transplantation*
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Male
  • Polymorphism, Genetic
  • Retrospective Studies
  • Tacrolimus / administration & dosage*
  • Tissue Donors

Substances

  • Immunosuppressive Agents
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Tacrolimus