Combivent - Clinical Pharmacology

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Pharmacokinetics

In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of two inhalations of Combivent Inhalation Aerosol to the two active components individually, the co-administration of ipratropium bromide and albuterol sulfate from a single canister did not significantly alter the systemic absorption of either component.

Ipratropium bromide levels remained below detectable limits (< 100 pg/ mL). Peak albuterol level obtained within 3 hours post-administration was 492 ± 132 pg/ mL. Following this single administration, 27.1 ± 5.7% of the estimated mouthpiece dose was excreted unchanged in the 24 hour urine. From a pharmacokinetic perspective, the synergistic efficacy of Combivent Inhalation Aerosol is likely to be due to a local effect on the muscarinic and beta 2 -adrenergic receptors in the lung.

Clinical Trials

In two 12-week randomized, double-blind, active-controlled clinical trials, 1067 patients with chronic obstructive pulmonary disease (COPD) were evaluated for the bronchodilator efficacy of Combivent Inhalation Aerosol (358 patients) in comparison to its components, ipratropium bromide (362 patients) and albuterol sulfate (347 patients).

Serial FEV1 measurements (shown below as a percent change from test-day baseline) demonstrated that Combivent Inhalation Aerosol produced significantly greater improvement in pulmonary function than either ipratropium bromide or albuterol sulfate when given separately. The median time to onset of a 15% increase in FEV1 was 15 minutes and the median time to peak FEV1 was one hour for Combivent Inhalation Aerosol and its components. The median duration of effect as measured by FEV1 was 4-5 hours for Combivent Inhalation Aerosol compared to 4 hours for ipratropium bromide and 3 hours for albuterol sulfate.

Percent Change in Adjusted Mean a FEV1 From Test-Day Baseline – Endpoint Analysis of the Evaluable Data Set

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These studies demonstrated that each component of Combivent Inhalation Aerosol contributed to the improvement in pulmonary function produced by the combination, especially during the first 4-5 hours after dosing, and that Combivent Inhalation Aerosol was significantly more effective than ipratropium bromide or albuterol sulfate administered alone.

In the two controlled twelve-week studies, Combivent Inhalation Aerosol did not produce any change in the secondary efficacy parameters including symptom scores, physician global assessments and morning PEFR, all of which were monitored throughout the study period.