Protection against methacholine-induced bronchospasm: salbutamol pMDIversusClickhaler® DPI

Abstract

Protection against methacholine-induced bronchospasm: salbutamol pMDI versus Clickhaler1 DPI. M.T. Newhouse, P. Patel, M. Parry-Billings. #ERS Journals Ltd 2003. ABSTRACT: Passive dry-powder inhalers (DPIs) have been developed as an alternative to pressurised metered-dose inhalers (pMDIs) to improve aerosol delivery on inhalation and eliminate the need for propellants. However, new DPI formulations of generic drugs must be rigorously compared with conventional pMDI therapy.This randomised, double-blind, double-dummy, placebo-controlled, seven-way crossover study evaluated bronchoprotection from methacholine challenge in order to compare a novel salbutamol DPI (Clickhaler1) with a reference salbutamol pMDI (Ventolin1). Adult asthma patients with airway hyperresponsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (PC20) v4 mg?mL -1 ) were treated on separate days with 0, 100, 200 or 400 mg of salbutamol via the DPI or pMDI. Methacholine challenge was performed before and after salbutamol treatment and the PC20 ratios analysed by Finney9s bioassay to test for therapeutic equivalence of the inhalers.Eighteen patients completed the study and showed significant dose-related responses to salbutamol. The relative potency of DPI:pMDI was 1.29 (90% confidence interval 1.04-1.63). There were no treatment differences in safety (cardiac frequency, blood pressure, adverse events).Methacholine-challenge methodology provides a sensitive bioassay and has demonstrated therapeutic equivalence of the salbutamol Clickhaler1 dry-powder inhaler with the conventional salbutamol pressurised metered-dose inhaler. Salbutamol, the b 2 -agonist bronchodilator most commonly used in the treatment of asthma, has been administered using pressurised metered-dose inhalers (pMDIs) and pressurised chlorofluorocarbon (CFC) propellants for the past 30 yrs. Substituting "ozone-friendly" alternatives puts the onus on the pharmaceutical industry to produce cost-effective replacement inhalers and establish that the switch-over from CFC pMDIs does not compromise patient care [1]. Each new device/formulation is a unique combination that must satisfy strict regulatory requirements [2].Pharmaceutical research and development has followed two major pathways: upgrading pMDIs with hydrofluoroalkanes (HFAs) as chlorine-free propellants, and innovative design of efficient dry-powder inhalers (DPIs) [3,4]. The activity of inhaled medications in the lung is determined by the amount of drug entering the lower respiratory tract [5], which is dependent on the mass of particles of y1-5 mm diameter and inspiratory flow velocity through the device [6]. Changes of formulation, humidity, device or handling may alter drug mass or deposition, with implications for both safety and efficacy [7][8][9]. Rapid systemic absorption of inhaled salbutamol occurs mainly at the vascular lung surface and the risk:benefit ratio can change with improved deposition [10]. In-vitro data therefore need the supp...

Effect of Study Design on Sample Size in Studies Intended to Evaluate Bioequivalence of Inhaled Short‐Acting β‐Agonist Formulations

“…In the case of methacholine challenge–based studies, measurement of each individual data point requires hours of study coordinator time. For these studies to succeed, study end points must be measured with maximal precision (minimal within‐subject variance) . Multiple, specialized, and highly trained study sites are needed and may be difficult for a study sponsor to identify.…”

Methacholine challenge tests to demonstrate therapeutic equivalence of terbutaline sulfate via different Turbuhaler ® devices in patients with mild to moderate asthma: Appraisal of a four-way crossover design

“…Bronchoprotection studies require a high degree of standardisation, with a double-blind, double-dummy design with at least two dose levels being recommended [4]. Accordingly, the present study was performed using this recommended design was used previously [1,5,9].…”