Model-informed drug development in pulmonary delivery: Preclinical pharmacokinetic-pharmacodynamic modelling for evaluation of treatments against chronic Pseudomonas aeruginosa lung infections.
- 作者列表："Sou TAS","Kukavica-Ibrulj I","Levesque RC","Friberg LE","Bergström CAS
: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 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) modelling. Plasma samples of tobramycin following pulmonary delivery via different types of dosing methods as well as growth and efficacy data from the chronic lung infection disease model following tobramycin treatment were collected for analysis and modelling. The developed PKPD model incorporates a semi-mechanistic description on biofilm development in chronic infections to allow a description 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 biofilm.
: 抗生素耐药性是世界范围内的主要公共卫生威胁，除其他外，约 80% 的囊性纤维化患者存在对当前许多抗生素耐药的慢性铜绿假单胞菌 (PA) 肺部感染。因此迫切需要新的治疗策略。对于肺部感染，将治疗直接递送到气道中的作用部位可以在最小全身暴露的情况下实现更高的局部浓度，从而避免不必要的全身不良反应的风险。以前，已经报道了 PA 慢性肺部感染的大鼠临床前疾病模型。然而，这种疾病模型在开发新治疗中的作用尚未得到彻底评估。在这项研究中，使用妥布霉素作为模型抗生素来评价这种临床前疾病模型在 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。收集不同给药方式肺部给药后妥布霉素的血浆样本以及妥布霉素治疗后慢性肺部感染疾病模型的生长和疗效数据进行分析和建模。开发的 PKPD 模型纳入了对慢性感染中生物膜发展的半机制描述，以允许描述药物对不同状态细菌的作用 (浮游、生物膜和潜伏)，并描述了功效研究的可用数据。PKPD 模型可以通过提供药物暴露-反应关系的定量描述和整合所有可用 PK 和 PKPD 的机制平台来支持临床前肺部感染疾病模型的应用。具有预测能力的数据。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，描述药物对生物膜的作用。
METHODS:BACKGROUND AND PURPOSE:A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD). EXPERIMENTAL APPROACH:C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed. KEY RESULTS:Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and α-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K2 , and S1P receptors (S1P2 and S1P3 ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice. CONCLUSIONS AND IMPLICATIONS:S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.
METHODS::The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.
METHODS::The respiratory tract is lined by a pseudo-stratified epithelium from the nose to terminal bronchioles. This first line of defense of the lung against external stress includes five main cell types: basal, suprabasal, club, goblet and multiciliated cells, as well as rare cells such as ionocytes, neuroendocrine and tuft/brush cells. At homeostasis, this epithelium self-renews at low rate but is able of fast regeneration upon damage. Airway epithelial cell lineages during regeneration have been investigated in the mouse by genetic labeling, mainly after injuring the epithelium with noxious agents. From these approaches, basal cells have been identified as progenitors of club, goblet and multiciliated cells, but also of ionocytes and neuroendocrine cells. Single-cell RNA sequencing, coupled to lineage inference algorithms, has independently allowed the establishment of comprehensive pictures of cell lineage relationships in both mouse and human. In line with genetic tracing experiments in mouse trachea, studies using single-cell RNA sequencing (RNAseq) have shown that basal cells first differentiate into club cells, which in turn mature into goblet cells or differentiate into multiciliated cells. In the human airway epithelium, single-cell RNAseq has identified novel intermediate populations such as deuterosomal cells, 'hybrid' mucous-multiciliated cells and progenitors of rare cells. Novel differentiation dynamics, such as a transition from goblet to multiciliated cells have also been discovered. The future of cell lineage relationships in the respiratory tract now resides in the combination of genetic labeling approaches with single-cell RNAseq to establish, in a definitive manner, the hallmarks of cellular lineages in normal and pathological situations.