Deferasirox pharmacogenetic influence on pharmacokinetic, efficacy and toxicity in a cohort of pediatric patients

Pharmacogenomics. 2017 Apr;18(6):539-554. doi: 10.2217/pgs-2016-0176. Epub 2017 Mar 27.

Abstract

Aim: We aimed to evaluate the influence of genetic polymorphisms involved in deferasirox metabolism and transport on its pharmacokinetics and treatment toxicity, in a cohort of β-thalassaemic children.

Patients & methods: Drug plasma concentrations were measured by a HPLC-UV method. Allelic discrimination for UGT1A1, UGT1A3, CYP1A1, CYP1A2, CYP2D6, MRP2 and BCRP1 polymorphisms was performed by real-time PCR.

Results: CYP1A1 rs2606345AA influenced Ctrough (p = 0.001) and t1/2 (p = 0.042), CYP1A1 rs4646903TC/CC (p = 0.005) and BCRP1 rs2231142GA/AA (p = 0.005) influenced Tmax and CYP2D6 rs1135840CG/GG influenced Cmax (p = 0.044). UGT1A1 rs887829TT (p = 0.002) and CYP1A2 rs762551CC (p = 0.019) resulted as predictive factor of ferritin levels and CYP1A1 rs2606345CA/AA (p = 0.021) and CYP1A2 rs762551AC/CC (p = 0.027) of liver iron concentration.

Conclusion: Our data suggest the usefulness of deferasirox pharmacogenetics in pediatric treatment optimization.

Keywords: BCRP1; CYP1A1; CYP1A2; CYP2D6; LIC; SNP; creatinine; ferritin; iron overload; β-thalassemia.

MeSH terms

  • Adolescent
  • Benzoates* / blood
  • Benzoates* / therapeutic use
  • Benzoates* / toxicity
  • Child
  • Child, Preschool
  • Cohort Studies
  • Deferasirox
  • Female
  • Humans
  • Iron Chelating Agents* / pharmacokinetics
  • Iron Chelating Agents* / therapeutic use
  • Iron Chelating Agents* / toxicity
  • Male
  • Pharmacogenomic Testing
  • Pharmacogenomic Variants*
  • Polymorphism, Single Nucleotide*
  • Triazoles* / blood
  • Triazoles* / therapeutic use
  • Triazoles* / toxicity
  • beta-Thalassemia / drug therapy*
  • beta-Thalassemia / genetics
  • beta-Thalassemia / metabolism

Substances

  • Benzoates
  • Iron Chelating Agents
  • Triazoles
  • Deferasirox