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Evaluation of the AERx Pulmonary Delivery System for Systemic Delivery of a Poorly Soluble Selective D-1 Agonist, ABT-431

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Abstract

Purpose. ABT-431 is a chemically stable, poorly soluble prodrug that rapidly converts in vivo to A-86929, a selective dopamine D-1 receptor agonist. This study was designed to evaluate the ability of the AERx™ pulmonary delivery system to deliver ABT-431 to the systemic circulation via the lung.

Methods. A 60% ethanol formulation of 50 mg/mL ABT-431 was used to prepare unit dosage forms containing 40 μL of formulation. The AERx system was used to generate a fine aerosol bolus from each unit dose that was collected either onto a filter assembly to chemically assay for the emitted dose or in an Andersen cascade impactor for particle size analysis. Plasma samples were obtained for pharmacokinetic analysis after pulmonary delivery and IV dosing of ABT-431 to nine healthy male volunteers. Doses from the AERx system were delivered as a bolus inhalation(s) (1, 2, 4, and 8 mg) and intravenous infusions were given over 1hr (5 mg). Pharmacokinetic parameters of A-86929 were estimated using noncompartmental analysis.

Results. The emitted dose was 1.02 mg (%RSD = 11.0, n = 48). The mass median aerodynamic diameter of the aerosol was 2.9 ± 0.1 μm with a geometric standard deviation of 1.3 ± 0.1 (n = 15). Tmax (mean ± SD) after inhalation ranged from 0.9 ± 0.6 to 11.5 ± 2.5. The mean absolute pulmonary bioavailibility (as A-86929) based on emitted dose ranged from 81.9% to 107.4%.

Conclusions. This study demonstrated that the AERx pulmonary delivery system is capable of reproducibly generating fine nearly monodisperse aerosols of a small organic molecule. Aerosol inhalation utilizing the AERx pulmonary delivery system may be an efficient means for systemic delivery of small organic molecules such as ABT-431.

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Authors and Affiliations

  1. Regulatory Affairs, Pain Therapeutics, Inc., S. San Francisco, California, 94080

    Franklin W. Okumu, Christine M. Woods & Reid Rubsamen

  2. Research and Development, Aradigm Corp., Hayward, California, 94545

    Rai-Yun Lee, James D. Blanchard, Anthony Queirolo, Jerry Okikawa, Stephen J. Farr & Reid Rubsamen

  3. Research and Development, Alexza Molecular Delivery Corp., Palo Alto, California, 94303

    Peter M. Lloyd

  4. Acrox Ltd., Melbourne, Australia

    Igor Gonda

  5. Research and Development, Aeropharm Technology, Inc., Edison, New Jersey, 08832

    Akwete L. Adjei & Richard J. Bertz

Authors
  1. Franklin W. Okumu
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  2. Rai-Yun Lee
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  3. James D. Blanchard
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  4. Anthony Queirolo
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  5. Christine M. Woods
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  6. Peter M. Lloyd
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  7. Jerry Okikawa
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  8. Igor Gonda
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  9. Stephen J. Farr
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  10. Reid Rubsamen
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  11. Akwete L. Adjei
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  12. Richard J. Bertz
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Correspondence to Franklin W. Okumu.

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Okumu, F.W., Lee, RY., Blanchard, J.D. et al. Evaluation of the AERx Pulmonary Delivery System for Systemic Delivery of a Poorly Soluble Selective D-1 Agonist, ABT-431. Pharm Res 19, 1009–1012 (2002). https://doi.org/10.1023/A:1016559707084

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  • DOI: https://doi.org/10.1023/A:1016559707084

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