Titre du document / Document title

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered-dose inhalers

Auteur(s) / Author(s)

CRETICOS Peter S. ⁽¹⁾ ; ADAMS Wallace P. ⁽²⁾ ; PETTY Brent G. ⁽³⁾ ; LEWIS Lionel D. ⁽³⁾ ; GUR JAI PAL SINGH ⁽⁴⁾ ; KHATTIGNAVONG Arouna P. ⁽¹⁾ ; MOLZON Justina A. ⁽⁵⁾ ; MARTINEZ Marilyn N. ⁽⁴⁾ ; LIETMAN Paul S. ⁽³⁾ ; WILLIAMS Roger L. ⁽²⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Medicine, Division of Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, ETATS-UNIS
⁽²⁾ Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, ETATS-UNIS
⁽³⁾ Department of Medicine. Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, ETATS-UNIS
⁽⁴⁾ Office of Generic Drugs. Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, ETATS-UNIS
⁽⁵⁾ Center for Drug Evaluation and Research, US Food and Drug Administration, Rockville, ETATS-UNIS

Résumé / Abstract

Background: 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. Objective: 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 ED₅₀, 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 I and 2 actuations. Methods: On separate study days, 15 nonsmokers with mild asthma received randomized nominal albuterol doses of 0 to 576 μg by using specially manufactured MDI canisters. FEV₁ was measured 15 minutes after MDI dosing. Serially increasing doses of methacholine were administered, and FEV₁ was measured after each methacholine dose until a 20% decrease in FEVI (PD₂₀) was achieved. Results: Mean PD₂₀ values after use of each of the albuterolcontaining MDIs were significantly greater than either mean screening or mean placebo PD₂₀values (P <.05). Mean responses and most individual subject responses to I and 2 actuations (90 and 180 μg) of albuterol MDI were within the sensitive region of the dose-response curve. The mean estimated ED₅₀ value on the basis of nonlinear mixed effect modeling was 119.2 μg (range, 33.3-337.1 μg), with an intersubject percentage coefficient of variation of 69.0%. Conclusions: 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.

Revue / Journal Title

Journal of allergy and clinical immunology   ISSN 0091-6749   CODEN JACIBY 

Source / Source

Congrès
Annual Meeting of the American Academy of Allergy and Immunology N^o50, Anaheim, CA , ETATS-UNIS (04/03/1994)
2002, vol. 110, n^o5, pp. 713-720 [8 page(s) (article)] (38 ref.)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, New York, NY, ETATS-UNIS  (1971) (Revue)

Mots-clés anglais / English Keywords

Immunopathology ; Obstructive pulmonary disease ; Respiratory disease ; Metered dose inhaler ; β2-Adrenergic receptor ; Salbutamol ; Agonist ; Antiasthma agent ; Spirometry ; Dose activity relation ; Provocation test ; Bioequivalence ; Methodology ; Chemotherapy ; Treatment ; Human ; Allergy ; Asthma ;

Mots-clés français / French Keywords

Immunopathologie ; Bronchopneumopathie obstructive ; Appareil respiratoire pathologie ; Aérosol doseur ; Récepteur β2-adrénergique ; Salbutamol ; Agoniste ; Antiasthmatique ; Spirométrie ; Relation dose réponse ; Test provocation ; Bioéquivalence ; Méthodologie ; Chimiothérapie ; Traitement ; Homme ; Allergie ; Asthme ;

Mots-clés espagnols / Spanish Keywords

Inmunopatología ; Broncopneumopatía obstructiva ; Aparato respiratorio patología ; Aerosol dosificador ; Receptor β2-adrenérgico ; Salbutamol ; Agonista ; Agente antiasma ; Espirometría ; Relación dosis respuesta ; Prueba provocación ; Bioequivalencia ; Metodología ; Quimioterapia ; Tratamiento ; Hombre ; Alergia ; Asma ;

Mots-clés d'auteur / Author Keywords

Asthma ; albuterol metered-dose inhaler ; bioequivalence ; dose-response ; methacholine challenge ;

Localisation / Location

INIST-CNRS, Cote INIST : 2059, 35400010549377.0050