A population analysis of nebulized (R)-albuterol in dogs using a novel mixed gut-lung absorption PK-PD model.
OBJECTIVE
The objectives of this study were to 1) construct a pharmacokinetic-pharmacodynamic (PK-PD) model, and 2) determine the PKs and PDs of (R)-albuterol when given by nebulization to 8 dogs for 7 consecutive days.


METHODS
Four doses were evaluated (0.002, 0.02, 0.1, and 0.4 mg/kg/ day). Blood samples were obtained after drug administration on days 1 and 7. Heart rates (HR) were obtained during treatment days 1, 4 and 7. All (R)-albuterol plasma concentrations were fitted using a mixed gut-lung absorption 2-compartment PK model. Day-1, 4, and 7 HR data were co-modeled using a direct response model with Hilltype equations, including a necessary tolerance phenomenon. The population PK-PD analysis was performed with an iterative 2-stage methodology (IT2S).


RESULTS
No chiral inversion was seen, and double absorption peaks on the plasma concentration versus time curves were observed in the majority of dogs. These were hypothesized to be the result of combined gut and lung absorption of (R)-Albuterol. Results indicated that 67% (range: 57-89%) of (R)-albuterol systemic exposure after nebulized administration is due to gut absorption. Mean population PK parameters were KaGI (10+/-5.7 h(-1)), KaLUNG (21+/-9.5 h(-1)), CLc/F (0.6+/-0.2 L/h/kg), CLd/F (1.4+/-0.5 L/h/kg), Vc/F (1.4+/-0.9 L/kg), and Vp/F (4.8+/-2.4 L/kg). (R)-albuterol administration was associated with an increase in the dogs heart rates. A tolerance effect related to the cumulative dose was observed and modeled.


CONCLUSIONS
The presented PK-PD model appears to differentiate gut from lung absorption when (R)-albuterol is given by 15-minute nebulization to dogs. These results agree with the accepted hypothesis that most of the systemic exposure of (R)-albuterol after nebulized administration is due to gut absorption.
Auclair
B
B
Faculté de Pharmacie, Université de Montréal, Canada.
Wainer
I W
IW
Fried
K
K
Koch
P
P
Jerussi
T P
TP
Ducharme
M P
MP
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000420:Albuterol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001825:Body Fluid Compartments; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007408:Intestinal Absorption; D008168:Lung / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009330:Nebulizers and Vaporizers; D013237:Stereoisomerism
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D000420:Albuterol