Population Pharmacokinetics and Bayesian Estimation of Tacrolimus Exposure in Renal Transplant Recipients on a New Once-Daily Formulation
Population Pharmacokinetics and Bayesian Estimation of Tacrolimus Exposure in Renal Transplant Recipients on a New Once-Daily Formulation
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DOI：
10.2165/11535950-000000000-00000
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发表时间：
2010-01-01
影响因子：
4.5
通讯作者：
Rousseau, Annick
中科院分区：
文献类型：
--
作者：
Benkali, Khaled;Rostaing, Lionel;Rousseau, Annick
背景和目标：新普乐可复（R）是他克莫司的一种新的缓释制剂，每日一次，他克莫司是一种广泛用于肾移植的强效免疫抑制剂。本研究的目的是（i）建立一个每日一次他克莫司在成人肾移植患者中的群体药代动力学模型;和（ii）建立一个贝叶斯估计器，能够可靠地估计个体药代动力学参数和暴露指数。从41例从环孢素转换为新的每日一次剂量的成人肾移植患者中获得的完整药代动力学特征-分析了超过6个月的每日他克莫司制剂。他克莫司的浓度用经验证的湍流色谱-串联质谱法测定。使用非线性混合效应建模软件（NONMEM（R）版本VI）计算群体参数。患者被随机分为（i）建模测试组（n=29）和（ii）验证组（n=12）。进行群体药代动力学分析，以估计人口统计学特征（性别、体重、年龄）、与泼尼松龙的药物相互作用、实验室检查结果（红细胞压积、血红蛋白水平和血清肌酐水平）和细胞色素P450（CYP）3A 5（CYP 3A 5）遗传多态性对他克莫司药代动力学的影响。通过考虑41例患者的所有数据进一步完善群体药代动力学模型，并使用自助法和访视预测检查验证最终模型。对于贝叶斯估计，最好的有限抽样策略的基础上确定的D-最优性标准和验证进行的validation group.Results：梯形面积全血浓度时间曲线从0到24小时（AUC（24））的他克莫司变化高达50%，为相同的谷浓度值。每日一次他克莫司的药代动力学可用二室模型结合Erlang分布来描述阿匹通相。CYP 3A 5基因型是最终模型中保留的唯一协变量。表达者（CYP 3A 5 *1/1和CYP 3A 5 */1/*3基因型）中他克莫司的表观清除率是非表达者（CYP 3A 5 *3/83基因型）的2倍。该因素解释了约25%的表观清除率个体间变异性。后验贝叶斯估计允许仅使用三个采样时间准确预测每日一次他克莫司的AUC（24（给药后0、1和3小时），非显著平均偏倚为0.7%（范围16-20%）和良好的精密度（均方根误差9%）。他克莫司每日一次在肾移植受者中的群体药代动力学分析导致确定CYP 3A 5 *1/* 3基因型作为他克莫司表观清除率的显著协变量，以及基于三个血药浓度测量值和该协变量设计准确的最大后验贝叶斯估计量。这种工具有助于比较不同的接触指数或不同的目标水平。这可能有助于改善某些患者每日一次他克莫司的疗效和耐受性。
Background and objectives: Advagraf (R) is a new extended-release once-daily formulation of tacrolimus, a potent immunosuppressant widely used in renal transplantation. The aims of this study were (i) to develop a population pharmacokinetic model for once-daily tacrolimus in adult renal transplant patients; and (ii) to develop a Bayesian estimator able to reliably estimate individual pharmacokinetic parameters and exposure indices.Methods: Full pharmacokinetic profiles obtained from 41 adult renal transplant patients who had been switched from ciclosporin to a single daily dose of the new once-daily tacrolimus formulation for more than 6 months were analysed. tacrolimus concentrations were measured using validated turbulent flow chromatography-tandem mass spectrometry methods. Population parameters were computed using non-linear mixed-effect modelling software (NONMEM (R) Version VI). The patients were randomly divided into (i) a model-building test group (n=29); and (ii) a validation group (n=12). Population pharmacokinetic analysis was performed to estimate the effects on tacrolimus pharmacokinetics of demographic characterstics (sex, bodyweight, age), drug interaction with prednisolone, laboratory test results (the haematocrit, haemaglobin level and serum creatinine level) and cytochrome P450 (CYP) 3A5 (CYP3A5) genetic polymorphism. The population pharmacokinetic model was further refined by taking into account all of the data from the 41 patients, and the final model was validated using a bootstrap and a visit predictive check. For Bayesian estimation, the best limited-sampling strategy was determined on the basis of the D-optimality criterion and validation performed in the validation group.Results: The trapezoidal area under the whole-blood concentration time curve from 0 to 24 hours (AUC(24)) of tacrolimus varied by up to 50% for the same trough concentration value. The pharmacokinetics of once-daily tacrolimus were well described by a two-compartment model combined with and Erlang distribution to describe the absorpiton phase. The CYP3A5 genotype was the only covariate retained in the final model. The apparent clearance of tacrolimus was 2-fold higher in expressers (with the CYP3A5*1/1 AND CYP3A5*/1/*3 genotypes) than in non-expressers (with the CYP3A5*3/83 genotype). This factor explained around 25% of the interindividual variability in the apparent clearance. A posteriori Bayesian estimation allowed accurate prediction of the AUC(24) of once-daily tacrolimus using just three sampling times (0, 1 and 3 hours post-dose) with a nonsignificant mean bias of 0.7% (range 16-20%) and good precision (root mean square error 9%).Conclusions: Population pharmacokinetic analysis of once-daily tacrolimus in renal transplant recipients resulted in identification of the CYP3A5*1/*3 genotype as a significant covariate on the apparent clearance of tacrolimus, and the design of an accurate maximum a posteriori Bayesian estimator based on three blood concentration measurements and this covariate. Such a tool could be helpful for comparing different exposure indices or different target levels. It could contribute to improvement of the efficacy and tolerability of once-daily tacrolimus in some patients.