肺输送中模型通知的药物开发：半机械药代动力学-药效学模型，用于评估慢性铜绿假单胞菌肺部感染的治疗。,Molecular Pharmaceutics

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肺输送中模型通知的药物开发：半机械药代动力学-药效学模型，用于评估慢性铜绿假单胞菌肺部感染的治疗。
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-17 , DOI: 10.1021/acs.molpharmaceut.9b00968
Tomás Sou _{1,

2} , Irena Kukavica-Ibrulj ₃ , Roger C Levesque ₃ , Lena E Friberg ₂ , Christel A S Bergström _{1,

4}

Affiliation

抗生素耐药性是全球范围内的主要公共卫生威胁，在其他囊性纤维化患者中，约80％的慢性铜绿假单胞菌（PA）肺部感染对多种当前的抗生素具有耐药性。因此，迫切需要新的治疗策略。对于肺部感染，将治疗直接递送至气道中的作用部位可实现较高的局部浓度，并使全身性暴露降至最低，从而避免了不良的全身性不良反应的风险。以前，已经报道了用于PA慢性肺部感染的大鼠临床前疾病模型。但是，这种疾病模型在开发新疗法中的作用尚未得到充分评估。在这项研究中，妥布霉素（TOB）被用作模型抗生素，以评估该临床前疾病模型在PA治疗中的应用。获得的数据用于药代动力学-药效学（PKPD）模型。收集了通过不同的给药方法进行肺部TOB递送后的血浆样品，以及经过TOB处理后来自慢性肺部感染疾病模型的生长和功效数据，以进行分析和建模。发达的PKPD模型结合了慢性感染生物膜形成的半机械描述，以评估药物对不同状态（即浮游生物，生物膜和潜伏状态）细菌的作用，并描述了功效研究的可用数据。通过提供对药物暴露-反应关系的定量描述以及将所有可用的PK和PKPD数据与预测能力进行整合的机制平台，PKPD模型可用于支持临床前肺部感染疾病模型的应用。在适当的实验设计的支持下，该模型可以进一步扩展到其他应用，例如研究细菌在状态之间的转换并描述药物对生物膜的作用。

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Model-Informed Drug Development in Pulmonary Delivery: Semimechanistic Pharmacokinetic-Pharmacodynamic Modeling for Evaluation of Treatments against Chronic Pseudomonas aeruginosa Lung Infections.

Antibiotic resistance is a major public health threat worldwide, and among others, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. Novel treatment strategies are therefore urgently needed. For lung infections, direct delivery of treatments to the site of action in the airway can achieve a higher local concentration with minimal systemic exposure and hence avoid risks of unwanted systemic adverse effects. Previously, a rat preclinical disease model for PA chronic lung infections has been reported. However, the role of this disease model in the development of new treatment has not been thoroughly evaluated. In this study, tobramycin (TOB) was used as a model antibiotic to evaluate the application of this preclinical disease model for PA treatments. The obtained data were used for pharmacokinetic-pharmacodynamic (PKPD) modeling. Plasma samples following pulmonary delivery of TOB via different dosing methods as well as growth and efficacy data from the chronic lung infection disease model following TOB treatments were collected for analysis and modeling. The developed PKPD model incorporates a semimechanistic description on biofilm development in chronic infections to allow the evaluation of drug action on bacteria in different states (i.e., planktonic, biofilm, and latent) and describes the available data from the efficacy study. The PKPD model can be used to support the application of the preclinical lung infection disease model by providing a quantitative description of the drug exposure-response relationship and a mechanistic platform to integrate all available PK and PKPD data with predictive capacity. With the support of appropriate experimental designs, the model can be further extended for other applications to, for instance, study the transition of bacteria between states and describe drug actions on biofilms.

更新日期：2020-01-17

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