Khaled Samer K, Palmer Joycelynne M, Herzog Josef, Stiller Tracey, Tsai Ni-Chun, Senitzer David, Liu Xueli, Thomas Sandra H, Shayani Sepideh, Weitzel Jeffrey, Forman Stephen J, Nakamura Ryotaro
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research of the Hematologic Malignancies and Stem Cell Transplantation Institute of the City of Hope, Duarte, CA.
Division of Biostatistics, City of Hope, Duarte, California.
Biol Blood Marrow Transplant. 2016 Feb;22(2):268-276. doi: 10.1016/j.bbmt.2015.08.027. Epub 2015 Aug 30.
Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/3 and CYP3A53/1 were associated with higher blood levels than CYP3A51/1 (P = .002). By multivariable analysis, rs776746 CYP3A53/3 and CYP3A53/1 were independently associated with decreased acute GVHD compared with CYP3A51/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.
涉及药物吸收、分布、代谢和排泄（ADME）的基因的等位基因变体决定了许多药物的药代动力学变异性，并且越来越被认为是决定医学治疗成败的重要因素。他克莫司和西罗莫司都有通过治疗药物监测（TDM）维持的狭窄治疗范围。使用一个覆盖了制药ADME工作组核心列表>99%的ADME检测板（36个药物遗传学相关基因中的188个单核苷酸多态性[SNP]和12个拷贝数变异[CNV]检测），我们研究了177例接受同种异体造血细胞移植（HCT）并使用基于他克莫司/西罗莫司的移植物抗宿主病（GVHD）预防方案的患者。我们测试了ADME变体与他克莫司/西罗莫司药物水平、浓度/剂量（C/D）比以及包括急性GVHD在内的临床终点之间可能存在的关联。在去除（几乎）所有样本中均为纯合的变体后，共有62个SNP和6个CNV检测可进行评估。对于西罗莫司，rs2032582（ABCB1）的T携带者与非T携带者相比，血药水平更高（P = 0.01），C/D比也有类似结果。广义估计方程分析支持了这些发现。对于他克莫司，rs776746 CYP3A⁵*3/3和CYP3A⁵3/1与CYP3A⁵1/1相比血药水平更高（P = 0.002）。通过多变量分析，在调整预处理、供体类型、种族/民族和年龄后，与CYP3A⁵1/1相比，rs776746 CYP3A⁵3/3和CYP3A⁵3/*1与急性GVHD发生率降低独立相关。尽管进行了TDM和剂量调整，我们仍证明了特定的ADME基因多态性与他克莫司/西罗莫司血药水平以及HCT后急性GVHD发生率之间的关联。一项正在进行的更大规模研究将确定这些关联在TDM之外是否具有临床实用性。
