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

Peter Socrates Creticos, Wallace P. Adams, Brent Gray Petty, Lionel D. Lewis, Gur Jai Pal Singh, Arouna P. Khattignavong, Justina A. Molzon, Marilyn N. Martinez, Paul S. Lietman, Roger L. Williams

Research output: Contribution to journalArticle

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 1 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 FEV1 (PD20) was achieved. Results: Mean PD20 values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD20 values (P <.05). Mean responses and most individual subject responses to 1 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.

Original languageEnglish (US)
Pages (from-to)713-720
Number of pages8
JournalThe Journal of Allergy and Clinical Immunology
Volume110
Issue number5
DOIs
StatePublished - Nov 2002

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Metered Dose Inhalers
Therapeutic Equivalency
Methacholine Chloride
Albuterol
Asthma
Placebos

Keywords

  • Albuterol metered-dose inhaler
  • Asthma
  • Bioequivalence
  • Dose-response
  • Methacholine challenge

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered-dose inhalers. / Creticos, Peter Socrates; Adams, Wallace P.; Petty, Brent Gray; Lewis, Lionel D.; Singh, Gur Jai Pal; Khattignavong, Arouna P.; Molzon, Justina A.; Martinez, Marilyn N.; Lietman, Paul S.; Williams, Roger L.

In: The Journal of Allergy and Clinical Immunology, Vol. 110, No. 5, 11.2002, p. 713-720.

Research output: Contribution to journalArticle

Creticos, Peter Socrates ; Adams, Wallace P. ; Petty, Brent Gray ; Lewis, Lionel D. ; Singh, Gur Jai Pal ; Khattignavong, Arouna P. ; Molzon, Justina A. ; Martinez, Marilyn N. ; Lietman, Paul S. ; Williams, Roger L. / A methacholine challenge dose-response study for development of a pharmacodynamic bioequivalence methodology for albuterol metered-dose inhalers. In: The Journal of Allergy and Clinical Immunology. 2002 ; Vol. 110, No. 5. pp. 713-720.
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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 1 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 FEV1 (PD20) was achieved. Results: Mean PD20 values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD20 values (P <.05). Mean responses and most individual subject responses to 1 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.",
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AU - Petty, Brent Gray

AU - Lewis, Lionel D.

AU - Singh, Gur Jai Pal

AU - Khattignavong, Arouna P.

AU - Molzon, Justina A.

AU - Martinez, Marilyn N.

AU - Lietman, Paul S.

AU - Williams, Roger L.

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N2 - 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 1 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 FEV1 (PD20) was achieved. Results: Mean PD20 values after use of each of the albuterol-containing MDIs were significantly greater than either mean screening or mean placebo PD20 values (P <.05). Mean responses and most individual subject responses to 1 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.

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