Tien Nguyen Tran Nam, Binh Vu Ngan, Ha Pham Thi Thanh, Lan Dang Thi Ngoc, Cho Yong-Soon, Long Nguyen Phuoc, Shin Jae-Gook, Anh Nguyen Hoang, Quan Truong Anh, Tuan Do Ngoc, Tiep Nguyen Khac, Thach Pham The, Anh Nguyen Hoang, Hoa Vu Dinh
National Drug Information and Adverse Drug Reactions Monitoring Centre, Hanoi University of Pharmacy, Hanoi, Vietnam.
Department of Analytical Chemistry and Drug Quality Control, Hanoi University of Pharmacy, Hanoi, Vietnam.
PLoS One. 2024 Dec 23;19(12):e0313764. doi: 10.1371/journal.pone.0313764. eCollection 2024.
Meropenem degradation poses a challenge to continuous infusion (CI) implementation. However, data about the impact of degradation on the probability of target attainment (PTA) of meropenem has been limited. This study evaluated the stability of meropenem brands and the consequence of in-bottle degradation on PTA in different environmental scenarios.
Seven meropenem generic brands prepared at concentrations of 1 g/48mL and 2 g/48mL in saline were examined at 25, 30, and 37°C over 8 h. A linear mixed-effects model was used to estimate degradation rate constant and potential covariates. In-bottle stability data was subsequently integrated as input for a deterministic and stochastic simulation using a published population pharmacokinetic model of critical illness. The impact of the degradation on target attainment at 98%fT>MIC was assessed.
Time, temperature, and infusion concentration were factors affecting the stability of the meropenem solution for all products. The differences in the degradation of seven generics were subtle, so their simulated plasma concentrations were equal. Meropenem CI with 8 h renewal infusion achieved a higher PTA than the extended 3 h infusion, even at the highest degradation condition. The impact of meropenem degradation on PTA was minimal vis-à-vis the meropenem dose, patient's renal function, and microbial susceptibility. Meropenem degradation reduced PTA by an observable magnitude in patients with augmented renal clearance and difficult-to-treat pathogens. Dose escalation up to 1.5-2g every 8 h could restore this reduction to the target 90% PTA.
Meropenem CI with 8 h of renewal infusion, considering stability even in tropical areas, was feasible to maximize the efficacy to difficult-to-treat pathogens.
美罗培南的降解对持续输注（CI）的实施构成挑战。然而，关于降解对美罗培南目标达成概率（PTA）影响的数据有限。本研究评估了不同环境场景下美罗培南各品牌的稳定性以及瓶内降解对PTA的影响。
将七种以1g/48mL和2g/48mL浓度在生理盐水中配制的美罗培南仿制药品牌，在25、30和37°C下进行8小时的检测。使用线性混合效应模型估计降解速率常数和潜在协变量。随后，将瓶内稳定性数据作为输入，用于使用已发表的危重病群体药代动力学模型进行确定性和随机模拟。评估了降解对98%fT>MIC时目标达成的影响。
时间、温度和输注浓度是影响所有产品中美罗培南溶液稳定性的因素。七种仿制药降解的差异细微，因此它们模拟的血浆浓度相等。即使在最高降解条件下，8小时更换输注的美罗培南CI比延长3小时输注实现了更高的PTA。美罗培南降解对PTA的影响相对于美罗培南剂量、患者肾功能和微生物敏感性而言最小。在肾清除率增加和病原体难以治疗的患者中，美罗培南降解使PTA降低了可观察到的幅度。每8小时剂量增加至1.5 - 2g可将这种降低恢复至目标PTA的90%。
考虑到即使在热带地区的稳定性，8小时更换输注的美罗培南CI对于使对难治疗病原体的疗效最大化是可行的。
