INSERM UMR-S850, University of Limoges, Limoges, France.
Ther Drug Monit. 2011 Apr;33(2):171-7. doi: 10.1097/FTD.0b013e31820d6ef7.
Several analytical techniques with different performances are available for the measurement of tacrolimus blood concentrations. The performance of Bayesian estimators (MAP-BEs) allowing dose adjustments of tacrolimus is dependent on the precision of the analytical technique. Hence, any Bayesian estimator should only be used for concentration data obtained with the same assay employed for its development. The present study aimed at evaluating the feasibility of developing Bayesian estimators dedicated to different immunoassays, using the concentrations obtained with the reference high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS) method and a simulation approach.
One hundred thirty-five full pharmacokinetic profiles of tacrolimus were obtained from 45 renal transplant patients using 3 different analytical techniques: 2 immunoassays [enzyme-multiplied immunoassay technique (EMIT) and chemiluminescent microparticle immunoassay (CMIA)] and LC-MS/MS. In a first step, 3 MAP-BEs were developed using the concentrations measured with the 3 techniques. Taking into account the correlation equations between the concentrations obtained with each of the immunoassays and LC-MS/MS, as well as the analytical error of the techniques, 2 hybrid MAP-BEs dedicated to the immunoassays were then developed after simulation of 100 pharmacokinetic profiles. Their performances were compared with those of the respective MAP-BEs developed using the actual immunoassay concentrations.
The mean concentrations measured over the dosing interval using EMIT and CMIA were significantly higher than those measured using LC-MS/MS (+15% and +11% in the AUC₀₋₂₄ h value, respectively, P < 0.0001), leading to differences in dose recommendations of -0.9 ± 1.1 and -0.7 ± 0.9 mg, respectively. When applying the MAP-BE developed from LC-MS/MS data for the EMIT or CMIA concentrations, tacrolimus AUC₀₋₂₄ h was estimated with an imprecision >20% in 33% and 27% of the patients, respectively. In contrast, the "CMIA" and "EMIT" hybrid MAP-BEs provided a good AUC₀₋₂₄ h estimation in 85%-93% of the patients.
This study showed the impact of the analytical technique on the performance of Bayesian estimators dedicated to tacrolimus dose adjustment and the feasibility to develop MAP-BE for a specific assay using results from a different assay, based on a limited method comparison study. This methodology could offer clinicians the opportunity to dose adjust tacrolimus whatever the assay used in their center.
有几种具有不同性能的分析技术可用于测量他克莫司的血药浓度。贝叶斯估计器（MAP-BE）的性能允许调整他克莫司的剂量，这取决于分析技术的精度。因此，任何贝叶斯估计器都只能用于为其开发所使用的相同检测方法获得的浓度数据。本研究旨在使用参考高效液相色谱-质谱检测（LC-MS/MS）方法和模拟方法，评估为不同免疫测定法开发专用贝叶斯估计器的可行性。
从 45 名肾移植患者中获得了 135 份完整的他克莫司药代动力学曲线，使用了 3 种不同的分析技术：2 种免疫测定法（酶放大免疫测定技术（EMIT）和化学发光微粒子免疫测定法（CMIA））和 LC-MS/MS。在第一步中，使用 3 种技术测量的浓度开发了 3 种 MAP-BE。考虑到每种免疫测定法与 LC-MS/MS 之间的浓度相关方程以及技术的分析误差，然后通过模拟 100 个药代动力学曲线，为免疫测定法开发了 2 种混合 MAP-BE。将它们的性能与使用实际免疫测定法浓度开发的各自 MAP-BE 进行了比较。
EMIT 和 CMIA 测量的剂量间隔内的平均浓度明显高于 LC-MS/MS 测量的浓度（AUC₀₋₂₄ h 值分别高 15%和 11%，P <0.0001），导致剂量建议分别为-0.9±1.1 和-0.7±0.9mg。当将来自 LC-MS/MS 数据的 MAP-BE 应用于 EMIT 或 CMIA 浓度时，在分别为 33%和 27%的患者中，他克莫司 AUC₀₋₂₄ h 的估计值的不精密度>20%。相比之下，“CMIA”和“EMIT”混合 MAP-BE 可在 85%-93%的患者中提供良好的 AUC₀₋₂₄ h 估计值。
本研究表明了分析技术对专用他克莫司剂量调整的贝叶斯估计器性能的影响，以及基于有限的方法比较研究，使用来自不同测定法的结果为特定测定法开发 MAP-BE 的可行性。该方法可为临床医生提供机会，无论其中心使用何种测定法，都可以调整他克莫司的剂量。
