AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients
AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients
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DOI：
10.1111/j.1523-1755.2005.00352.x
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发表时间：
2005-06-01
影响因子：
19.6
通讯作者：
de Fijter, JW
中科院分区：
文献类型：
--
作者：
Scholten, EM;Cremers, SCLM;de Fijter, JW
背景。他克莫司具有狭窄的治疗窗口，并且已知在肾移植受者之间的生物利用度差异很大。大多数研究中心仍然依赖于低谷水平的测量，但关于他克莫司低谷水平与全身暴露之间的相关性存在相互矛盾的报告。通过浓度随时间变化曲线下面积（AUC((0-12 h))）测定。我们开发并验证了一个基于双区室人群的药代动力学模型，该模型具有他克莫司全身暴露的贝叶斯估计。随后，我们使用该模型在15个连续的肾移植受者中应用auc引导剂量的他克莫司。主要目的是研究患者在一段时间内的变异性。贝叶斯预测采用两点采样策略，波谷水平，并在给药后2至4小时获得第二个样本，显著提高了与AUC的平方相关性（(0-12h)） （r(2) = 0.94）。与槽位监测相比，该方法将95%-预测区间缩短了50%。贝叶斯方法在临床实践中被证明是可行的，并提供了个体患者全身他克莫司暴露的准确信息。在auc指导的给药队列中，他克莫司的表观清除率随着时间的推移逐渐降低，但没有反映在相应的低谷水平。这种简单、灵活的方法提供了定制免疫抑制的机会，并应有助于减少他克莫司相关的毒性，如肾毒性和移植后糖尿病。
Background. Tacrolimus has a narrow therapeutic window, and bioavailability is known to vary considerably between renal transplant recipients. Most centers still rely on measurement of trough levels, but there are conflicting reports on the correlation between tacrolimus trough levels and systemic exposure. as measured by the area-under-the -concemration-over-time curve (AUC((0-12 h))).Methods. We developed and validated a two-compartmental population-based pharmacokinetic model with Bayesian estimation of tacrolimus systemic exposure. Subsequently, we used this model to apply prospectively AUC-guided dosing of tacrolimus in 15 consecutive renal transplant recipients. The main objective was to study intrapatient variability in the course of time.Results. Bayesian forecasting with a two-point sampling strategy, a trough level, and a second sample obtained between two and four hours post-dose significantly improved the squared correlation with the AUC((0-12h)) (r(2) = 0.94). Compared with trough level monitoring only, this approach reduced the 95%-prediction interval by 50%. The Bayesian approach proved to be feasible in clinical practice, and provided accurate information about systemic tacrolimus exposure in individual patients. In the AUC-guided dosing cohort the apparent clearance of tacrolimus decreased gradually over time, which was not reflected in corresponding trough levels.Conclusion. This simple, flexible method provides the opportunity to tailor immunosuppression, and should help minimize tacrolimus-related toxicity, such as nephrotoxicity and post-transplant diabetes mellitus.