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CYP3A4/5 genotypes and age codetermine tacrolimus concentration and dosage in pediatric heart transplant recipients

Li Liu1, Xiao Huang1, Ying Zhou1

  • 1Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China.

International Immunopharmacology
|August 23, 2022
PubMed

Insights

Tacrolimus (TAC) dosing in pediatric heart transplant recipients is complex due to age and genetic factors. Age and CYP3A4/5 genetic variants significantly impact TAC levels and required doses, but not acute kidney injury.

Area of Science:

  • Pharmacogenomics
  • Pediatric Transplantation
  • Immunosuppression Management

Background:

  • Tacrolimus (TAC) is crucial for immunosuppression after pediatric heart transplantation (HTx).
  • Optimizing TAC dosage is challenging due to limited understanding of developmental and genetic influences on its pharmacokinetics.
  • Early post-operative period is critical for TAC management.

Purpose of the Study:

  • To investigate the combined effects of genetic polymorphisms and age on TAC concentrations and dosage in pediatric HTx recipients.
  • To evaluate the relationship between genotypes, age, TAC dose-adjusted trough concentrations (C0/D), dose requirements, and acute kidney injury (AKI).

Main Methods:

  • Sixty-six pediatric HTx recipients were grouped by age: <6, ≥6-≤12, and 12-18 years.
  • Genotyping was performed for CYP3A4/5, POR, and ABCB1 polymorphisms.
  • Associations between genotypes, age, TAC C0/D, dose, and AKI were analyzed.

Main Results:

  • CYP3A5*3 and CYP3A4*1G genotypes correlated with TAC C0/D and dose requirements in recipients aged ≥6 years.
  • TAC C0/D was 2.8-fold and 4.2-fold higher in children aged ≥6-≤12 and 12-18 years, respectively, compared to those <6 years.
  • TAC dose requirements were 2.4 times and 3.5 times higher in children <6 years compared to those aged ≥6-≤12 and 12-18 years, respectively.
  • Within specific genotypes (CYP3A5*3 or CYP3A4*1G), increasing age correlated with higher TAC C0/D and lower target doses.
  • No significant association was found between genetic variants and AKI in the early post-operative period.

Conclusions:

  • Age and CYP3A4/5 genotypes are significant factors influencing TAC disposition in pediatric HTx recipients.
  • Individualized TAC dosing strategies should consider both patient age and specific CYP3A4/5 genetic profiles.
  • Further research may be needed to explore other factors influencing TAC pharmacokinetics and AKI risk.

Keywords:
AgeCYP3A4*1GCYP3A5*3Pediatric Heart TransplantationTacrolimus

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