Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans.
The purpose of this study was to evaluate the feasibility of intrapulmonary delivery of ABT-431, a selective D1 receptor agonist. Following intratracheal instillation of the drug solution, the lung bioavailability was found to be approximately 75% in dogs. An aerosol suspension formulation was then developed by dispersing the drug in tetrafluoroethane, HFC-134a, with the aid of poloxamer 124 and vitamin E. This ABT-431 MDI aerosol formulation showed about 40% of the particles emitted from the valve and actuator system to be under 5 microm in diameter. Also, the primary package (15 mL aluminum container, DF10/ACT-150 valve, and Micron-4-actuator with the orifice 0.4 mm) was satisfactory for accurate and reproducible dosimetry. Using tracheostomized beagle dogs, the C(max) following tracheal administration of 5 mg aerosolized ABT-431 was found to be 13.3+/-0.9 ng ml(-1) and the AUC(0-24) was estimated at 33.2+/-10.6 h ng ml(-1). The lung bioavailability of the aerosolized drug was 34% compared to intravenous injection in dogs. In humans, results from a single rising dose study demonstrated that rapid absorption of ABT-431 following oral inhalation administration resulted in a dose-dependent increase in the area under the plasma-time curve at dosage levels between 3.3 and 13.2 mg. There is a possibility of up to 25% absorption of the drug from human lung. Thus, pulmonary bioavailability of ABT-431 is significantly greater than that of oral administration. Also, these findings suggest that small and lipophilic compounds, especially with hepatic first pass effect, may be effectively delivered systemically using oral inhalation aerosols.
Zheng
Y
Y
Pharmaceutical Products Division, Formulation Development Center, Abbott Laboratories, 1401 Sheridan Road, North Chicago, IL 60064-6246, USA. jack.zheng@abbott.com
Marsh
K C
KC
Bertz
R J
RJ
El-Shourbagy
T
T
Adjei
A L
AL
D000042:Absorption; D000328:Adult; D000335:Aerosol Propellants; D000336:Aerosols; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D004285:Dogs; D018491:Dopamine Agonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004311:Double-Blind Method; D006801:Humans; D007275:Injections, Intravenous; D008168:Lung / Q000378:metabolism*; D008297:Male; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015363:Quinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000335:Aerosol Propellants; D000336:Aerosols; D018491:Dopamine Agonists; D011355:Prodrugs; D011725:Pyridines; D015363:Quinolones; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C095428:adrogolide hydrochloride; C095427:A 86929