Das Shampa, Riccobene Todd, Carrothers Timothy J, Wright James G, MacPherson Merran, Cristinacce Andrew, McFadyen Lynn, Xie Rujia, Luckey Alison, Raber Susan
AstraZeneca, Alderley Park, Macclesfield, UK.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
Eur J Clin Pharmacol. 2024 Apr;80(4):529-543. doi: 10.1007/s00228-023-03609-x. Epub 2024 Jan 22.
A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections.
Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection.
Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies.
A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program.
NCT01689207; NCT02655419; NCT03329092; NCT03580044.
基于新出现的数据进行了一系列迭代群体药代动力学（PK）建模和目标达成概率（PTA）分析，以支持氨曲南-阿维巴坦（一种用于治疗严重革兰氏阴性菌感染的研究性联合抗生素）的剂量选择。
在联合PTA分析（主要目标：氨曲南60%的fT＞8mg/L，阿维巴坦50%的fT＞2.5mg/L）中，使用了基于感染患者的阿维巴坦数据和具有“类患者”假设的健康受试者的氨曲南数据构建的两轮PK模型，以探索患者变异性、输注持续时间以及中度（估计肌酐清除率[CrCL]＞30至≤50mL/min）和重度肾功能损害（＞15至≤30mL/min）的调整。剂量选择时考虑联合PTA＞90%的达成情况以及不同肾清除率的影响。
I/IIa期剂量选择/调整的第一轮模拟表明，3小时输注和持续输注提供了相当的PTA；阿维巴坦剂量在临床相关暴露目标范围内驱动联合PTA；负荷剂量支持更快地联合达到目标。选择了氨曲南/阿维巴坦500/137mg 30分钟负荷剂量和1500/410mg 3小时维持输注，每6小时一次，用于进一步评估。使用扩展PK模型的第二轮模拟支持了方案变更（500/167mg负荷；对于CrCL＞50mL/min，1500/500mg每6小时一次维持3小时输注）以及IIa/III期临床研究中肾功能损害的剂量选择。
氨曲南-阿维巴坦以3:1的固定比例每6小时一次给予负荷剂量加3小时维持输注可优化联合PTA。这些分析支持了氨曲南-阿维巴坦III期临床项目的剂量选择。
NCT01689207；NCT02655419；NCT03329092；NCT03580044。
