Zaltzman Alina S R, Glick Lauren A, Zaltzman Jeffrey S, Nash Michelle, Huang Michael, Prasad G V Ramesh
Faculty of Medicine, University of Ottawa, Ottawa, Canada.
Faculty of Medicine, University of Toronto, Toronto, Canada.
Transplant Res. 2016 Jan 28;5:2. doi: 10.1186/s13737-016-0031-6. eCollection 2016.
Tacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD.
A cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA.
Conversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort.
The CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements.
Clinical trials.gov identifier: NCT01884480.
他克莫司有每日两次给药的普乐可复（Tac-BID）和每日一次给药的新山地明（Advagraf，Tac-OD）两种剂型。尽管它们在治疗上等效，但一些移植受者在两种剂型转换后需要调整剂量，以达到相似的他克莫司谷浓度（Tac C0）。他克莫司主要通过细胞色素P450 3A5（CYP3A5）代谢。我们试图确定CYP3A5酶的基因多态性，即CYP3A5 *1/*1和CYP3A5 *1/*3（表达者）与CYP3A5 *3/*3（非表达者）相比，是否可以解释从Tac-BID转换为Tac-OD后剂量需求的差异。
在我们对496例患者进行的更大规模转换研究中，选取60例肾移植受者（RTR）队列进行CY3A5基因多态性的额外检测。分析内容包括人口统计学、他克莫司给药情况、转换前后的Tac C0以及相对于CYP3A5基因型的给药变化。通过对基因组DNA的分析确定CYP3A5基因多态性。
该队列从他克莫司每日两次给药转换为每日一次给药时，平均（标准差）剂量需要从3.1（1.0）mg/天增加到3.8（1.3）mg/天（p = 0.007），以达到相似的Tac C0。与CYP3A5 *3/*3非表达者组（26.6%）相比，CYP3A5 *1/*3表达者组在从Tac-BID转换为Tac-OD时需要更大百分比的剂量调整（56.7%）。在两个表达者组（CYP3A5 *1/*1和CYP3A5 *1/*3）合并时也观察到了类似结果。在东亚队列中，表达者的比例显著更高。
CYP3A5表达者多态性使得从Tac-BID转换为Tac-OD时需要增加剂量，表达者基因型对这一结果有显著影响。鉴于不同种族群体中CYP3A5基因型频率的差异，未来研究在优化给药需求时应考虑同工酶多态性和种族因素。
ClinicalTrials.gov标识符：NCT01884480。
