de Velde Femke, de Winter Brenda C M, Neely Michael N, Strojil Jan, Yamada Walter M, Harbarth Stephan, Huttner Angela, van Gelder Teun, Koch Birgit C P, Muller Anouk E
Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Department of Hospital Pharmacy, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.
Pharmaceutics. 2021 Dec 16;13(12):2170. doi: 10.3390/pharmaceutics13122170.
Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90-120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.
群体药代动力学建模与模拟（M&S）用于优化抗生素给药方案。关于参数化和非参数化M&S之间的差异，人们所知甚少。我们的目标是比较：（1）重症患者亚胺培南参数化和非参数化模型的外部验证；（2）使用两种模型的模拟计算目标达成概率（PTA）。所使用的M&S软件为NONMEM 7.2（参数化）和Pmetrics 1.5.2（非参数化）。两种模型的外部预测性能对于估算肾小球滤过率（eGFR）≥78 mL/min的患者是足够的，但对于较低eGFR的患者则不足，这表明（使用eGFR≥60 mL/min的群体开发的）模型不能外推至较低的eGFR。针对三种给药方案和三种eGFR（90、120、150 mL/min）进行了模拟。两种模型50%的PTA结果相似，而另外50%的结果中，非参数化模型得出的最低抑菌浓度（MIC）较低。这可以通过非参数化模型中更高的受试者间变异性估计值来解释。模拟表明，对于eGFR为90 - 120 mL/min的患者，每6小时静脉滴注1000 mg可达到2 mg/L的MIC。对于4 mg/L的MIC以及更高的eGFR，由于每个模型的PTA值差异很大，目前尚无给药建议。临床实践中不同建模方法的影响应进一步研究。
