Holz O, Tan L, Schaumann F, Müller M, Scholl D, Hidi R, McLeod A, Krug N, Hohlfeld J M
Fraunhofer Institute of Toxicology and Experimental Medicine (ITEM), Clinical Airway Research, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research, Hannover, Germany.
Pfizer Ltd., Clinical Research, Sandwich, Kent, UK.
Pulm Pharmacol Ther. 2015 Dec;35:50-9. doi: 10.1016/j.pupt.2015.10.011. Epub 2015 Nov 10.
Segmental endotoxin challenge with lipopolysaccharide (LPS) can be used as a pharmacodynamic model to safely induce a transient airway inflammation in the peripheral lung of healthy subjects and to test the anti-inflammatory efficacy of investigational new drugs. In contrast to whole lung LPS challenge only a fraction of the dose is required that can be precisely administered to a specific lung region and a vehicle challenged segment as an intra-subject control can be included. The aim of this study was to assess the intra- and inter-individual variability of the response to segmental LPS challenge for the appropriate design and power calculation of future clinical trials. Two cohorts with 10 subjects each underwent two segmental LPS challenges within five weeks. The inflammatory response was evaluated in bronchoalveolar lavage (BAL) fluid at 6 (cohort 1) and 24 h (cohort 2) both in the LPS and in a vehicle challenged segment, as well as in plasma for up to 26 h post LPS challenge. While the cytokine response was more pronounced at 6 h, the influx of neutrophils and monocytes dominated at 24 h; e.g. neutrophils increased from a median (inter-quartile range, IQR) of 0.14 (0.16) and 0.09 (0.08)x10(4) cells/mL BAL fluid at baseline to 10.2 (17.1) and 19.3 (15.9)x10(4) cells/mL 24 h after the two separate challenges. The within-subject variability was higher than the between-subject variability for most of the markers. However, sample size estimations based on the variability of outcome variables found lower or equal numbers with cross-over designs compared to parallel group designs for cellular markers at 24 h and cytokine variables at 6 h. The segmental LPS challenge model was safe. Future study designs have to balance between burden to the study subjects (4 versus 2 bronchoscopies), variability (within-versus between-subject), and the desired outcome variable (cells versus chemo/cytokine).
用脂多糖（LPS）进行节段性内毒素激发可作为一种药效学模型，用于在健康受试者的外周肺中安全诱导短暂性气道炎症，并测试研究性新药的抗炎疗效。与全肺LPS激发相比，所需剂量仅为其一小部分，且该剂量可精确施用于特定肺区域，还可纳入一个用赋形剂激发的节段作为受试者内对照。本研究的目的是评估对节段性LPS激发反应的个体内和个体间变异性，以便为未来临床试验进行适当的设计和功效计算。两个队列各有10名受试者，在五周内接受了两次节段性LPS激发。在LPS激发节段和赋形剂激发节段，于激发后6小时（队列1）和24小时（队列2）对支气管肺泡灌洗（BAL）液中的炎症反应进行评估，并在LPS激发后长达26小时对血浆中的炎症反应进行评估。虽然细胞因子反应在6小时时更为明显，但中性粒细胞和单核细胞的流入在24小时时占主导；例如，在两次单独激发后24小时，中性粒细胞从基线时BAL液中中位数（四分位间距，IQR）为0.14（0.16）和0.09（0.08）×10⁴个细胞/mL，增加至10.2（17.1）和19.3（15.9）×10⁴个细胞/mL。对于大多数标志物，个体内变异性高于个体间变异性。然而，基于结局变量变异性的样本量估计发现，与平行组设计相比，交叉设计在24小时时细胞标志物和6小时时细胞因子变量的所需样本量更低或相等。节段性LPS激发模型是安全的。未来的研究设计必须在研究对象的负担（4次与2次支气管镜检查）、变异性（个体内与个体间）和期望的结局变量（细胞与化学物质/细胞因子）之间进行权衡。
