Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany.
Research DMPK, Drug Discovery Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
J Antimicrob Chemother. 2022 Oct 28;77(11):2922-2932. doi: 10.1093/jac/dkac240.
Treating pulmonary infections by administering drugs via oral inhalation represents an attractive alternative to usual routes of administration. However, the local concentrations after inhalation are typically not known and the presumed benefits are derived from experiences with drugs specifically optimized for inhaled administration.
A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to elucidate the pulmonary PK for ciprofloxacin, rifampicin and tigecycline and link it to bacterial PK/PD models. An exemplary sensitivity analysis was performed to potentially guide drug optimization regarding local efficacy for inhaled antibiotics.
Detailed pulmonary tissue, endothelial lining fluid and systemic in vivo drug concentration-time profiles were simultaneously measured for all drugs in rats after intravenous infusion. Using this data, a PBPK/PD model was developed, translated to humans and adapted for inhalation. Simulations were performed comparing potential benefits of oral inhalation for treating bronchial infections, covering intracellular pathogens and bacteria residing in the bronchial epithelial lining fluid.
The PBPK/PD model was able to describe pulmonary PK in rats. Often applied optimization parameters for orally inhaled drugs (e.g. high systemic clearance and low oral bioavailability) showed little influence on efficacy and instead mainly increased pulmonary selectivity. Instead, low permeability, a high epithelial efflux ratio and a pronounced post-antibiotic effect represented the most impactful parameters to suggest a benefit of inhalation over systemic administration for locally acting antibiotics.
The present work might help to develop antibiotics for oral inhalation providing high pulmonary concentrations and fast onset of exposure coupled with lower systemic drug concentrations.
通过口服吸入给药来治疗肺部感染，是一种有吸引力的替代常规给药途径的方法。然而，吸入后局部浓度通常未知，并且假定的益处来自于专门针对吸入给药优化的药物的经验。
开发了一种基于生理的药代动力学/药效学（PBPK/PD）模型，以阐明环丙沙星、利福平、替加环素的肺部 PK，并将其与细菌 PK/PD 模型联系起来。进行了示例性的敏感性分析，以潜在地指导吸入抗生素局部疗效的药物优化。
在大鼠体内静脉输注后，同时测量所有药物在肺部组织、内皮衬里液和全身的详细药物浓度-时间曲线。利用这些数据，开发了一种 PBPK/PD 模型，将其转化为人类，并适用于吸入。模拟比较了口服吸入治疗支气管感染、覆盖细胞内病原体和位于支气管上皮衬里液中的细菌的潜在益处。
PBPK/PD 模型能够描述大鼠肺部 PK。常用于口服吸入药物的优化参数（如高全身清除率和低口服生物利用度）对疗效影响不大，而主要增加了肺部选择性。相反，低通透性、高上皮外排比和明显的抗生素后效应是表明吸入相对于全身给药对局部作用抗生素具有益处的最具影响力的参数。
本研究可能有助于开发用于口服吸入的抗生素，提供高肺部浓度和快速暴露起始，同时降低全身药物浓度。
