Evaluation of the AERx pulmonary delivery system for systemic delivery of a poorly soluble selective D-1 agonist, ABT-431.
OBJECTIVE
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 microL 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 1 hr (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 microm 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.
Regualatory Affairs, Pain Therapeutics, Inc, San Francisco, California 94080, USA. fokumu@yahoo.com
Franklin W
FW
Okumu
Rai-Yun
RY
Lee
James D
JD
Blanchard
Anthony
A
Queirolo
Christine M
CM
Woods
Peter M
PM
Lloyd
Jerry
J
Okikawa
Igor
I
Gonda
Stephen J
SJ
Farr
Reid
R
Rubsamen
Akwete L
AL
Adjei
Richard J
RJ
Bertz
D000280:Administration, Inhalation; D019540:Area Under Curve; D018491:Dopamine Agonists / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D008297:Male; D036501:Metered Dose Inhalers / Q000706:statistics & numerical data; D010316:Particle Size; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D012995:Solubility; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry
D018491:Dopamine Agonists; D011725:Pyridines; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; C095428:adrogolide hydrochloride