Department of Pharmacology and Toxicology, CHU Limoges.
IPPRITT, Université de Limoges, INSERM, Limoges.
Ther Drug Monit. 2021 Aug 1;43(4):472-480. doi: 10.1097/FTD.0000000000000828.
Immunosuppressant Bayesian Dose Adjustment (ISBA) is an online expert system that estimates the area under the curve (AUC) of immunosuppressive drugs through pharmacokinetic modelling and Bayesian estimation to propose dose adjustments to reach predefined exposure targets. The ISBA database was retrospectively analyzed to describe tacrolimus pharmacokinetics and exposure, evaluate the efficiency of ISBA dose recommendations, and propose tacrolimus AUC0-12h target ranges for pediatric renal allograft recipients treated with immediate release tacrolimus.
The database included 1935 tacrolimus dose adjustment requests from 419 patients <19 years old who were treated with immediate-release tacrolimus and followed in 21 French hospitals. The tacrolimus exposure evolution with patient age and posttransplantation time, the correlation between trough tacrolimus concentration (C0) and AUC0-12h at different periods posttransplantation, and the efficiency of dose recommendations to avoid underexposure and overexposure and to decrease between-patient AUC variability were investigated.
Tacrolimus AUC showed large between-patient variability (CV% = 40%) but moderate within-patient variability (median = 24.3% over a 3-month period). Dose-standardized exposure but not the AUC/C0 ratio significantly decreased with time posttransplantation and patient age. We derived AUC0-12h ranges from the consensual C0 ranges using linear regression equations. When the ISBA recommended dose was applied, the AUC distribution was narrower and a significantly higher proportion was within the targets (P < 0.0001).
ISBA efficiently reduced tacrolimus underexposure and overexposure. The AUC0-12h target ranges for pediatric patients derived from the database were similar to those previously reported for adults. Estimating the AUC/C0 ratio could help determine personalized C0 targets.
免疫抑制剂贝叶斯剂量调整（ISBA）是一种在线专家系统，通过药代动力学建模和贝叶斯估计来估算免疫抑制剂的曲线下面积（AUC），从而提出剂量调整以达到预设的暴露目标。对 ISBA 数据库进行了回顾性分析，以描述他克莫司的药代动力学和暴露情况，评估 ISBA 剂量建议的效率，并为接受即时释放他克莫司治疗的小儿肾移植受者提出他克莫司 AUC0-12h 目标范围。
该数据库包括来自 21 家法国医院的 419 名年龄小于 19 岁的患者的 1935 次他克莫司剂量调整请求。研究了患者年龄和移植后时间对他克莫司暴露的影响，移植后不同时期的谷浓度（C0）与 AUC0-12h 的相关性，以及避免暴露不足和过度以及降低患者间 AUC 变异性的剂量建议的效率。
他克莫司 AUC 表现出较大的个体间变异性（CV%=40%），但个体内变异性适中（3 个月期间中位数为 24.3%）。与移植后时间和患者年龄相比，剂量标准化的暴露而不是 AUC/C0 比值显著降低。我们使用线性回归方程从共识的 C0 范围中得出 AUC0-12h 范围。当应用 ISBA 推荐剂量时，AUC 分布更窄，且显著更高比例在目标范围内（P<0.0001）。
ISBA 有效地减少了他克莫司的暴露不足和过度。从数据库中得出的小儿患者的 AUC0-12h 目标范围与以前报道的成人相似。估计 AUC/C0 比值有助于确定个性化的 C0 目标。
