Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients

International Journal of Molecular Sciences

卷:21

J.Ryan Shaw¹  DanielJ. Crona²  JohnL. Schmitz²  JonathanR. Ptachcinski³  MauriceD. Alexander³  ThomasC. Shea³  JordanA. Miller³  Tatjana Grgic³  Tim Wiltshire³  PaulM. Armistead⁴  JamesM. Coghill⁴  MarcieL. Riches⁴  KatarzynaJ. Jamieson⁴  JonathanS. Serody⁴  Oscar Suzuki⁴  KamakshiV. Rao⁴  WilliamA. Wood⁴  Tejendra Patel⁵  Jing Zhu⁵  Mehak Aggarwal⁵  BenjaminG. Vincent⁵  MargaretR. Sketch⁵  ChadD. Torrice⁵  EricT. Weimer⁵ 

[1] Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;

[2] Department of Pathology &

[3] Department of Pharmacy, University of North Carolina Hospitals and Clinics, Chapel Hill, NC 27599, USA;

[4] Division of Hematology and Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA;

[5] The Center for Pharmacogenomics and Individualized Therapy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC 27599, USA;

关键词: tacrolimus;    pharmacogenetics;    pharmacokinetics;    pharmacodynamics;    allogeneic hematopoietic stem cell transplant;    single nucleotide polymorphism (snp);    germline;    cyp3a4/5;    abcb1;   

DOI  :  10.3390/ijms21030858

来源: DOAJ

【 摘 要 】

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

【 授权许可】

Unknown