Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease
Longitudinal FEV1 dose-response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease
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DOI：
10.1007/s10928-012-9274-0
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发表时间：
2012-12-01
影响因子：
2.5
通讯作者：
Ribbing, Jakob
中科院分区：
文献类型：
--
作者：
Nielsen, Jace C.;Hutmacher, Matthew M.;Ribbing, Jakob
本研究的目的是描述两种吸入长效β受体激动剂(PF-00610355和沙美特罗)与1秒用力呼气量(FEV_1)之间的剂量-反应关系，以便为慢性阻塞性肺疾病患者未来的临床试验提供剂量建议。这项对四项研究的荟萃分析包括来自690名中度COPD患者的8513次FEV1测量。建立了纵向动力学-药效学(K-PD)模型，并充分描述了FEV1测量随时间的变化，包括一天内的昼夜模式，以及服用PF-00610355或沙美特罗引起的FEV1测量的变化。细颗粒剂量，即存在于小到足以肺部递送的颗粒中的药物数量，被用作PF-00610355的暴露测量。在磨合过程中服用短效β激动剂后，可逆性更强，与FEV1对长效β激动剂的反应增加(通过增加最大反应E-max)有关。为了更好地了解PF-00610355相对于安慰剂和沙美特罗的反应，进行了模拟。模拟的结果表明，每天服用一次28.1微克的细颗粒物与安慰剂相比，在低谷时平均改善超过100毫升的可能性中等。另一方面，50微克的细颗粒剂量与低谷时的安慰剂相比，改善120毫升的可能性大于0.78。从疗效的角度来看，假设第三阶段制剂的细颗粒比例为25%；每天一次的标称剂量为100和200微克，将有兴趣在未来的第三阶段试验中进行研究。
The objective of this work was to characterize the dose-response relationship between two inhaled long-acting beta agonists (PF-00610355 and salmeterol) and the forced expiratory volume in one second (FEV1) in order to inform dosing recommendations for future clinical trials in patients with chronic obstructive pulmonary disease (COPD). This meta-analysis of four studies included 8,513 FEV1 measurements from 690 patients with moderate COPD. A longitudinal kinetic-pharmacodynamic (K-PD) model was developed and adequately described changes in FEV1 measurements over time, including circadian patterns within a day, as well as changes in FEV1 measurements elicited from administration of PF-00610355 or salmeterol. The fine-particle dose, the amount of drug present in particles small enough for lung delivery, was used as the exposure measure for PF-00610355. Greater reversibility following administration of a short-acting beta agonist during run-in was associated with increased FEV1 response to long-acting beta agonists (through an increased maximal response, E-max). Simulations were conducted to better understand the response to PF-00610355 relative to placebo and salmeterol. The results of the simulations show that once daily fine-particle doses of 28.1 mu g versus placebo have a moderate probability of providing an average improvement above 100 mL at trough. The 50 mu g fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120 mL improvement versus placebo at trough. From an efficacy perspective and assuming a fine-particle fraction of 25 % for the Phase 3 formulation; 100 and 200 mu g once daily nominal doses would be of interest to investigate in future Phase 3 trials.