Faculté de Pharmacie, Université de Montréal, Montréal, Québec, Canada.
Department of Pharmacy, McGill University Health Center, Montréal, Québec, Canada.
Pediatr Pulmonol. 2020 May;55(5):1154-1160. doi: 10.1002/ppul.24689. Epub 2020 Mar 2.
In patients with cystic fibrosis (CF), amikacin is the alternative for the treatment of acute pulmonary exacerbations associated with pathogens resistant to tobramycin. Population pharmacokinetic (PK) models of amikacin in adult patients with CF have been previously published. However, current dosing recommendations remain disputed (Illamola et al. Clin Pharmacokinet. 2018;57(10):1217-1228). We perform here the first external evaluation of a published amikacin adult CF population PK model and propose a dosing nomogram for initial dosing.
We retrospectively collected demographic, biological, and clinical data from the medical records of adult patients who had received intravenous amikacin. To assess the predictive performance of this model we applied visual comparison of predictions to observations, calculation of bias and inaccuracy, and simulation-based diagnostics. Monte Carlo simulations from the evaluated model were used to compare maximum concentration/minimum inhibitory concentration achieved with different dosing regimens.
A total of 91 concentrations from 19 adult patients with CF were collected for external evaluation. The model predicted amikacin concentrations with reasonable bias (7.2% [95% confidence interval, CI: -0.7% to 15.0%]) and inaccuracy (18.2% [95% CI: 12.0%-24.4%]). Our simulations with this model suggest that administered amikacin doses must be adjusted to creatinine clearance and also adjusted to body weight (doses from 20 to 45 mg/kg/d). According to these simulations, we developed the Montreal amikacin nomogram to optimize amikacin dosing regimens in patients with CF.
In conclusion, we developed the first nomogram to optimize initial amikacin dosing regimens in patients with CF based on this external evaluation of a recently published amikacin population PK model.
在囊性纤维化（CF）患者中，当存在对妥布霉素耐药的病原体时，阿米卡星是治疗急性肺部恶化的替代药物。先前已经发表了 CF 成年患者阿米卡星的群体药代动力学（PK）模型。然而，目前的剂量推荐仍存在争议（Illamola 等人，Clin Pharmacokinet. 2018；57（10）：1217-1228）。我们在此首次对已发表的 CF 成年人群 PK 模型进行了外部评估，并提出了初始剂量的剂量方案图。
我们从接受静脉注射阿米卡星的成年 CF 患者的病历中回顾性收集了人口统计学、生物学和临床数据。为了评估该模型的预测性能，我们应用了观察预测值的视觉比较、偏差和不准确性的计算以及基于模拟的诊断。从评估模型中进行的蒙特卡罗模拟用于比较不同剂量方案下达到的最大浓度/最小抑菌浓度。
共收集了 19 名 CF 成年患者的 91 个浓度进行外部评估。该模型对阿米卡星浓度的预测具有合理的偏差（7.2%[95%置信区间，CI：-0.7%至 15.0%]）和不准确性（18.2%[95%CI：12.0%-24.4%]）。我们使用该模型进行的模拟表明，必须根据肌酐清除率和体重调整给予的阿米卡星剂量（剂量范围为 20 至 45mg/kg/d）。根据这些模拟，我们制定了蒙特利尔阿米卡星方案图，以优化 CF 患者的阿米卡星剂量方案。
总之，我们基于最近发表的阿米卡星群体 PK 模型的外部评估，为 CF 患者制定了第一个优化初始阿米卡星剂量方案的方案图。
