Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Orlando, Florida, USA.
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Antimicrob Agents Chemother. 2023 May 17;67(5):e0019723. doi: 10.1128/aac.00197-23. Epub 2023 Apr 6.
Polymyxin B is a "last-line-of-defense" antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens. A linear 1-compartment model, plus an epithelial lining fluid (ELF) compartment for the lung model, best described the PK. Clearance and volume of distribution were similar among the four components. The bioavailability fractions were 72.6% for polymyxin B1, 12.0% for B1-Ile, 11.5% for B2, and 3.81% for B3 for the lung model and were similar for the bloodstream model. While the volume of distribution was comparable between both models (17.3 mL for the lung and 27 mL for the bloodstream model), clearance was considerably smaller for the lung (2.85 mL/h) compared to that of the bloodstream model (5.59 mL/h). The total drug exposure (AUC) in ELF was high due to the saturable binding of polymyxin B presumably to bacterial lipopolysaccharides. However, the modeled unbound AUC in ELF was ~16.7% compared to the total drug AUC in plasma. The long elimination half-life (4 h) of polymyxin B enabled humanized dosage regimens with every 12 h dosing in mice. Daily doses that optimally matched the range of drug concentrations observed in patients were 21 mg/kg for the bloodstream and 13 mg/kg for the lung model. These dosage regimens and population PK models support translational studies for polymyxin B at clinically relevant drug exposures.
多粘菌素 B 是一种“最后一线”抗生素，于 20 世纪 60 年代获得批准。然而，其四种主要成分在感染小鼠中的群体药代动力学（PK）尚未报道。我们旨在确定多粘菌素 B1、B1-Ile、B2 和 B3 在鲍曼不动杆菌血流和肺部感染模型中的 PK，并制定人性化的剂量方案。线性 1 房室模型，加上肺部模型的上皮衬液（ELF）室，最能描述 PK。四种成分的清除率和分布容积相似。生物利用度分数分别为肺部模型中多粘菌素 B1 为 72.6%、B1-Ile 为 12.0%、B2 为 11.5%、B3 为 3.81%，血流模型相似。虽然两个模型的分布容积相似（肺部为 17.3 mL，血流模型为27 mL），但肺部清除率明显较小（2.85 mL/h），而血流模型为 5.59 mL/h。由于多粘菌素 B 与细菌脂多糖的结合可能是饱和的，因此 ELF 中的总药物暴露量（AUC）很高。然而，模拟的 ELF 中未结合的 AUC 与血浆中的总药物 AUC 相比约为 16.7%。多粘菌素 B 的长消除半衰期（4 h）使得在小鼠中每 12 h 给药的人性化剂量方案成为可能。最佳匹配患者观察到的药物浓度范围的每日剂量为血流模型 21 mg/kg 和肺部模型 13 mg/kg。这些剂量方案和群体 PK 模型支持在临床相关药物暴露下进行多粘菌素 B 的转化研究。
