Institute of Clinical Pharmacology, Santa Maria della Misericordia University Hospital of Udine, Udine, Italy; Department of Medicine, University of Udine, Udine, Italy.
Department of Medicine, Section of Statistics, University of Udine, Udine, Italy.
Int J Antimicrob Agents. 2017 Jul;50(1):23-28. doi: 10.1016/j.ijantimicag.2017.01.036. Epub 2017 May 8.
This study aimed to develop clinically feasible models of limited sampling strategy (LSS) for estimation of the area under the concentration-time curve (AUC) for isoniazid, that could be applied easily in daily clinical practice for dosage adjustment in adult patients with tuberculosis. Isoniazid plasma concentrations (n = 1665) from 185 adult tuberculous patients were used for the development and validation of LSS models to estimate AUC following administration of the standard 5 mg/kg dose of isoniazid. Population pharmacokinetic analysis for appropriate estimation of isoniazid pharmacokinetic parameters was performed in a modelling group (n = 100). The Bayesian estimates of AUC (AUC) obtained for each individual were used as the dependent variable in the regression analysis for the development of various LSS models. The LSS models were validated in a separate cohort (n = 85). Several three and four time point LSS models were built and tested. Model H (AUC = -1.88 + 1.05 × C + 0.78 × C + 9.44 × C) and Model I (AUC= -0.65 + 1.00 × C + 1.94 × C + 15.45 × C) had the best performances [adj-R = 0.93, median prediction error (MPE) = -0.20, root median squared prediction error (RMSE) = 4.65 for Model H; adj-R = 0.96, MPE = -0.05 RMSE = 3.56 for Model I]. The very high R values (≥0.94) of these regression equations in the validation cohort confirmed their high reliability. These LSS models could be applied in the context of therapeutic drug monitoring programmes aiming to personalize isoniazid dosing regimens for adult patients with tuberculosis.
本研究旨在开发一种临床可行的限采样策略（LSS）模型，用于估算异烟肼的浓度-时间曲线下面积（AUC），以便在日常临床实践中轻松应用于调整成人肺结核患者的剂量。 来自 185 例成年结核患者的异烟肼血浆浓度（n=1665）用于开发和验证 LSS 模型，以估算标准 5mg/kg 异烟肼剂量给药后的 AUC。 在建模组（n=100）中进行群体药代动力学分析以适当估算异烟肼药代动力学参数。 每位个体的 AUC（AUC）的贝叶斯估计值被用作回归分析中各个 LSS 模型的因变量。 在单独的队列（n=85）中验证了 LSS 模型。 构建并测试了几种三时间点和四时间点 LSS 模型。 模型 H（AUC=-1.88+1.05×C+0.78×C+9.44×C）和模型 I（AUC=-0.65+1.00×C+1.94×C+15.45×C）表现最佳[调整 R=0.93，中值预测误差（MPE）=-0.20，根均方预测误差（RMSE）=4.65 用于模型 H；调整 R=0.96，MPE=-0.05 RMSE=3.56 用于模型 I]。 验证队列中这些回归方程的非常高 R 值（≥0.94）证实了它们的高可靠性。 这些 LSS 模型可应用于治疗药物监测计划，旨在为成人肺结核患者个性化异烟肼给药方案。
