Lesche Dorothea, Sigurdardottir Vilborg, Setoud Raschid, Oberhänsli Markus, Carrel Thierry, Fiedler Georg M, Largiadèr Carlo R, Mohacsi Paul, Sistonen Johanna
*Institute of Clinical Chemistry, University Hospital (Inselspital Bern), and University of Bern; †Graduate School for Cellular and Biomedical Sciences, University of Bern; and Departments of ‡Cardiology, and §Cardiovascular Surgery, Swiss Cardiovascular Centre, University Hospital (Inselspital Bern), Bern, Switzerland.
Ther Drug Monit. 2014 Dec;36(6):710-5. doi: 10.1097/FTD.0000000000000080.
After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and under-immunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients.
Associations between 7 functional genetic variants and blood dose-adjusted trough (C0) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively.
Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/1 genotype) required around 2.2- to 2.6-fold higher daily TAC doses to reach the targeted C0 concentration at all studied time points (P ≤ 0.003). Additionally, the POR28 variant carriers showed higher dose-adjusted TAC-C0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement.
The CYP3A53 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.
心脏移植（HTx）后，免疫抑制药物的个体间药代动力学变异性是一个重大的治疗挑战，因为免疫抑制过度导致毒性与免疫抑制不足导致移植物排斥之间的治疗窗很窄。尽管基因多态性已被证明会影响免疫抑制剂的药代动力学，但HTx背景下的数据却很稀少。因此，我们评估了CYP3A4、CYP3A5、POR、NR1I2和ABCB1基因变异在免疫抑制药物途径中共同作用对HTx受者他克莫司（TAC）和环孢素（CSA）剂量需求的影响。
分别在52例和45例患者队列中评估了7种功能性基因变异与HTx后1、3、6和12个月时TAC和CSA的血药剂量调整谷浓度（C0）之间的关联。
与CYP3A5非表达者（*3/*3基因型）相比，CYP3A5表达者（*1/3或1/1基因型）在所有研究时间点达到目标C0浓度所需的每日TAC剂量高出约2.2至2.6倍（P≤0.003）。此外，POR28变异携带者在所有时间点的剂量调整TAC-C0浓度均较高，导致HTx后3个月（P = 0.025）和6个月（P = 0.047）出现显著差异。未观察到基因变异与CSA剂量需求之间的显著关联。
CYP3A53变异对HTx受者所需的TAC剂量有重大影响，而POR28可能额外导致了观察到的变异性。这些结果支持了基因标记在HTx后TAC剂量优化中的重要性。
