Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients.
Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients.
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DOI：
10.1002/jcph.1118
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发表时间：
2018-09
影响因子：
2.9
通讯作者：
Tornatore KM
中科院分区：
文献类型：
--
作者：
Campagne O;Mager DE;Brazeau D;Venuto RC;Tornatore KM
他克莫司表现出患者间药代动力学变异性，这归因于CYP3A5同工酶和外排转运蛋白p -糖蛋白。大多数非裔美国肾移植受者需要比白人更高的他克莫司剂量，以达到类似的波谷，当使用种族调整的建议。已建立的指南提供了基于CYP3A5*1（W/T）和蛋白质功能变异丧失的他克莫司基因型剂量建议：CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343)，并可能提供更全面的种族调整剂量建议。我们的目的是建立一个他克莫司人群药代动力学模型，评估稳定的非裔美国人和白人肾移植受者的人口学、临床和基因组因素。第二个目的是研究基于种族的他克莫司方案和基因型特异性给药。67名接受口服他克莫司和霉酚酸治疗≥6个月的受试者完成了一项12小时的药代动力学研究。CYP3A5*3、*6、*7和ABCB1 1236T>C、2677T>GA、3435T>C多态性。使用一种新的CYP3A5*3*6*7代谢组合物将患者分为广泛代谢者、中度代谢者和低代谢者。采用NONMEM 7.3软件进行建模和仿真。具有一阶消除和时滞吸收的两室模型最好地描述了数据。CYP3A5*3*6*7代谢复合物与他克莫司清除率显著相关（p值<0.05），在广泛代谢者（平均44.3 L∙hr−1）和中等代谢者（28.6 L∙hr−1）中清除率比差代谢者（19.7 L∙hr−1）更快。模拟支持基于CYP3A5*3*6*7基因型的他克莫司剂量增加一般种族调整方案，中等和广泛代谢物的剂量分别增加1.5倍和2倍，与低代谢物暴露相当。该模型提供了一种新的方法来确定他克莫司剂量调整，以保持具有不同CYP3A5基因型的非裔美国人和白人受体之间可比较的治疗暴露。
Tacrolimus exhibits inter-patient pharmacokinetic variability attributed to CYP3A5 isoenzymes and the efflux transporter, P-glycoprotein. Most African American renal transplant recipients require higher tacrolimus doses compared to whites to achieve similar troughs when race-adjusted recommendations are used. An established guideline provides tacrolimus genotype dosing recommendations based on CYP3A5*1(W/T) and loss of protein function variants: CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272), CYP3A5*7 (rs41303343) and may provide more comprehensive race-adjusted dosing recommendations. Our objective was to develop a tacrolimus population pharmacokinetic model evaluating demographic, clinical and genomic factors in stable African American and white renal transplant recipients. A secondary objective investigated race-based tacrolimus regimens and genotype-specific dosing. Sixty-seven recipients receiving oral tacrolimus and mycophenolic acid ≥ 6 months completed a 12-hour pharmacokinetic study. CYP3A5*3,*6,*7 and ABCB1 1236T>C, 2677T>GA, 3435T>C polymorphisms were characterized. Patients were classified as extensive, intermediate and poor metabolizers using a novel CYP3A5*3*6*7 metabolic composite. Modeling and simulation was performed with NONMEM 7.3. A two-compartment model with first-order elimination and absorption with lag time best described the data. The CYP3A5*3*6*7 metabolic composite was significantly associated with tacrolimus clearance (P-value<0.05), which was faster in extensive (mean: 44.3 L∙hr−1) and intermediate (28.6 L∙hr−1) metabolizers than poor metabolizers (19.7 L∙hr−1). Simulations support CYP3A5*3*6*7 genotype-based tacrolimus dosing to enhance general race-adjusted regimens, with dose increases of 1.5-fold and 2-fold, respectively, in intermediate and extensive metabolizers for comparable exposures to poor metabolizers. This model offers a novel approach to determine tacrolimus dosing adjustments that maintain comparable therapeutic exposure between African American and white recipients with different CYP3A5 genotypes.
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影响因子：
8.8
作者：
Matas, A. J.;Smith, J. M.;Kasiske, B. L.
通讯作者：
Kasiske, B. L.
影响因子：
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作者：
Jacobson PA;Oetting WS;Brearley AM;Leduc R;Guan W;Schladt D;Matas AJ;Lamba V;Julian BA;Mannon RB;Israni A;DeKAF Investigators
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通讯作者：
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作者：
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通讯作者：
Halloran, Philip F.
影响因子：
3.4
作者：
Antignac, Marie;Barrou, Benoit;Urien, Saik
通讯作者：
Urien, Saik