Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.
Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.
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本研究调查了稳定肾移植受者中他克莫司药代动力学和药效学的种族和性别差异。进行了一项横断面、开放标签、单中心、12小时药代动力学-药效学研究。他克莫司药代动力学参数包括浓度-时间曲线下面积（AUC 0 -12）、AUC 0 -4、12 h谷值（C 12 h）、最大浓度（Cmax）、口服清除率（Cl）、剂量标准化AUC 0 -12、谷值和Cmax以及标准化不良反应评分。使用统计模型分析终点，并进行个体协变量调整，包括临床因素、基因型变异体CYP 3A 5 *3、CYP 3A 5 *6、CYP 3A 5 *7（CYP 3A 5 *3*6*7）代谢复合物和ATP结合盒基因亚家族B成员1（ABCB 1）多态性。对65例在移植后≥6个月接受他克莫司和霉酚酸的稳定的女性和男性、黑人和白色人肾移植受者进行了评价。黑人受体表现出较高的他克莫司AUC 0 -12（人种：p = 0.005）、较低的AUC*（人种：p < 0.001;人种×性别：p = 0.068）和较高的Cl（人种：p < 0.001;性别：p = 0.066）。更大累积（性别：p < 0.001;种族×性别：p = 0.014）、神经系统（性别：p = 0.021;种族×性别：p = 0.005）和美学（性别：p = 0.002）不良反应，黑人女性得分最高。84.8%的黑人患者和68.8%的白色患者达到了目标AUC 0 -12（p = 0.027）。在31.3%的白色受体和9.1%的黑人受体中，尽管他克莫司谷值在目标范围内，但AUC 0 -12 <100 ng·h/ml（p = 0.027）。新型CYP 3A 5 *3*6*7代谢复合物是占他克莫司剂量变异性15%-19%（p = 0.002）、AUC 0 -12 h*（p < 0.001）和Cl（p < 0.001）的显著协变量。他克莫司的药代动力学和不良反应在稳定的肾移植受者组中不同，基于种族和性别，患者间变异性与CYP 3A 5 *3*6*7代谢复合物相关。在女性中观察到更多的累积、神经系统和美学不良反应。考虑种族和性别的他克莫司方案可能会减少不良反应，并通过促进更多患者达到目标AUC 0 -12 h来提高移植物结局。
This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. A cross‐sectional, open‐label, single center, 12‐h pharmacokinetic‐pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration‐time curve (AUC0–12), AUC0–4, 12‐h troughs (C 12 h), maximum concentrations (C max), oral clearance (Cl), with dose‐normalized AUC0–12, troughs, and C max with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate‐adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms. 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post‐transplant were evaluated. Black recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p < 0.001), and Cl (p < 0.001). Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h.
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DOI：
10.1111/j.1600-6143.2009.03009.x
发表时间：
2010-04
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Fan PY;Ashby VB;Fuller DS;Boulware LE;Kao A;Norman SP;Randall HB;Young C;Kalbfleisch JD;Leichtman AB
通讯作者：
Leichtman AB
影响因子：
6.7
作者：
de Jonge, H.;de Loor, H.;Kuypers, D. R.
通讯作者：
Kuypers, D. R.
影响因子：
8.8
作者：
Ekberg, H.;Bernasconi, C.;Halloran, P. F.
通讯作者：
Halloran, P. F.
影响因子：
8.8
作者：
Hart, A.;Lentine, K. L.;Snyder, J. J.
通讯作者：
Snyder, J. J.
影响因子：
158.5
作者：
Ekberg, Henrik;Tedesco-Silva, Helio;Halloran, Philip F.
通讯作者：
Halloran, Philip F.