School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, People's Republic of China.
Clin Pharmacokinet. 2022 Oct;61(10):1427-1441. doi: 10.1007/s40262-022-01161-y. Epub 2022 Aug 10.
The combination of polymyxins, meropenem, and sulbactam demonstrated efficacy against multi-drug-resistant bacillus Acinetobacter baumannii. These three antibiotics are commonly used against major blood, skin, lung, and heart muscle infections.
The objective of this study was to predict drug disposition and extrapolate the efficacy in these tissues using a physiologically based pharmacokinetic modeling approach that linked drug exposures to their target pharmacodynamic indices associated with antimicrobial activities against A. baumannii.
An adult physiologically based pharmacokinetic model was developed for meropenem, colistin, and sulbactam and scaled to pediatrics accounting for both renal and non-renal clearances. The model reliability was evaluated by comparing simulated plasma and tissue drug exposures to observed data. Target pharmacodynamic indices were used to evaluate whether pediatric and adult dosing regimens provided sufficient coverage.
The modeled plasma drug exposures in adults and pediatric patients were consistent with reported literature data. The mean fold errors for meropenem, colistin, and sulbactam were in the range of 0.710-1.37, 0.981-1.47, and 0.647-1.39, respectively. Simulated exposures in the blood, skin, lung, and heart were consistent with reported penetration rates. In a virtual pediatric population aged from 2 to < 18 years, the interpretive breakpoints were achieved in 85-90% of subjects for their targeted pharmacodynamic indices after administration of pediatric dosing regimens consisting of 30 mg/kg of meropenem, and 40 mg/kg of sulbactam three times daily as a 3-h or continuous infusion and 5 mg/kg/day of colistin base activity.
The physiologically based pharmacokinetic modeling supports pediatric dosing regimens of meropenem/colistin/sulbactam in a co-administration setting against infections in the blood, lung, skin, and heart tissues due to A. baumannii.
黏菌素、美罗培南和舒巴坦的联合使用已被证明对多重耐药鲍曼不动杆菌具有疗效。这三种抗生素常用于治疗主要的血液、皮肤、肺部和心肌感染。
本研究旨在通过生理基于药代动力学模型方法预测药物分布，并推断其在血液、肺部、皮肤和心脏组织中的疗效。该方法将药物暴露与抗鲍曼不动杆菌的抗菌活性相关的目标药效学指标联系起来。
建立了美罗培南、黏菌素和舒巴坦的成人生理基于药代动力学模型，并通过考虑肾和非肾清除率将其扩展到儿科。通过比较模拟血浆和组织药物暴露与观察数据来评估模型的可靠性。使用目标药效学指标来评估儿科和成人给药方案是否提供了足够的覆盖范围。
成人和儿科患者的模型血浆药物暴露与文献报道的数据一致。美罗培南、黏菌素和舒巴坦的平均倍数误差分别在 0.710-1.37、0.981-1.47 和 0.647-1.39 范围内。血液、皮肤、肺部和心脏的模拟暴露与报道的穿透率一致。在一个年龄从 2 岁到 < 18 岁的虚拟儿科人群中，在给予儿科剂量方案后，85-90%的目标药效学指标达到了判断标准。该剂量方案为：美罗培南 30mg/kg，每日三次，持续 3 小时或连续输注；舒巴坦 40mg/kg，每日三次；黏菌素 base 活性 5mg/kg/天。
生理基于药代动力学模型支持美罗培南/黏菌素/舒巴坦在联合给药时用于治疗因鲍曼不动杆菌引起的血液、肺部、皮肤和心脏组织感染的儿科剂量方案。
