Creticos Peter S, Adams Wallace P, Petty Brent G, Lewis Lionel D, Singh Gur Jai Pal, Khattignavong Arouna P, Molzon Justina A, Martinez Marilyn N, Lietman Paul S, Williams Roger L
Department of Medicine, Division of Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Allergy Clin Immunol. 2002 Nov;110(5):713-20. doi: 10.1067/mai.2002.129036.
With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation.
In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albuterol as delivered by MDI. Sensitivity was assessed in terms of magnitudes of ED(50), the estimated albuterol dose required to achieve 50 % of the fitted maximal value of the pharmacodynamic effect above baseline, and change in response as a function of dose, with emphasis on 1 and 2 actuations.
On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 microg by using specially manufactured MDI canisters. FEV(1) was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV(1) was measured after each methacholine dose until a 20 % decrease in FEV(1) (PD(20)) was achieved.
Mean PD(20) values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD(20) values (P <.05). Mean responses and most individual subject responses to 1 and 2 actuations (90 and 180 microg) of albuterol MDI were within the sensitive region of the dose- response curve. The mean estimated ED(50) value on the basis of nonlinear mixed effect modeling was 119.2 microg (range, 33.3-337.1 microg), with an intersubject percentage coefficient of variation of 69.0 %.
The methacholine bronchoprovocation model is safe and useful in the study of albuterol MDI dose-response in asthmatic subjects. Bronchoprovocation studies may be used for determination of bioequivalence of multisource albuterol MDI products.
随着沙丁胺醇定量吸入器（MDIs）专利在1989年到期，评估通用制剂体内生物等效性的方法需要进行研究。
为了开发一种灵敏的方法来证明生物等效性，使用氯化乙酰甲胆碱进行支气管激发试验来评估MDI递送的沙丁胺醇的剂量-反应关系。敏感性通过ED(50)的大小来评估，ED(50)是指达到高于基线的药效学效应拟合最大值的50%所需的估计沙丁胺醇剂量，以及作为剂量函数的反应变化，重点是1次和2次喷雾。
在不同的研究日，15名患有轻度哮喘的非吸烟者使用特制的MDI药罐接受随机的名义沙丁胺醇剂量，范围为0至576微克。MDI给药15分钟后测量第一秒用力呼气容积（FEV(1)）。依次给予递增剂量的乙酰甲胆碱，并在每次给予乙酰甲胆碱后测量FEV(1)，直到FEV(1)下降20%（PD(20)）。
使用每种含沙丁胺醇的MDI后的平均PD(20)值显著高于平均筛查或平均安慰剂PD(20)值（P<.05）。沙丁胺醇MDI 1次和2次喷雾（90和180微克）的平均反应以及大多数个体受试者的反应都在剂量-反应曲线的敏感区域内。基于非线性混合效应模型的平均估计ED(50)值为119.2微克（范围为33.3 - 337.1微克），受试者间百分比变异系数为69.0%。
乙酰甲胆碱支气管激发试验模型在哮喘患者中研究沙丁胺醇MDI剂量-反应方面是安全且有用的。支气管激发试验可用于确定多源沙丁胺醇MDI产品的生物等效性。
