Pharmacokinetics of Salbutamol Delivered from the Unit Dose Dry Powder Inhaler: Comparison with the Metered Dose Inhaler and Diskus Dry Powder Inhaler.
OBJECTIVE
To compare the systemic exposure of salbutamol following delivery from the unit dose dry powder inhaler (UD-DPI) system with that from the Diskus®and metered dose inhaler (MDI).


METHODS
This open-label, two-part, six-way crossover, randomized single-dose study in healthy subjects evaluated salbutamol systemic exposure of three dose strengths (using three inhalations: 3 × 150 μg [450 μg], 3 × 200 μg [600 μg], and 3 × 250 μg [750 μg]) and 2% of drug in lactose blends (1.6% and 1.0% [600 μg dose only] by weight) following delivery through the UD-DPI compared with systemic exposure from the Diskus and MDI (600 μg dose). Systemic exposure in the presence of charcoal block was also evaluated. Primary treatment comparisons were area under the concentration-time curve from time zero to 12 hours [AUC0-12] and maximum plasma concentration [Cmax].


RESULTS
Delivery of salbutamol 600 μg from the UD-DPI resulted in total systemic exposure similar to that from the Diskus and approximately half of that from the MDI (AUC0-12geometric least squares mean ratio [GMR] [90% confidence interval (CI)] for UD-DPI [1.6% blend]/Diskus: 0.91 [0.83-1.00]; UD-DPI [1.6% blend]/MDI: 0.46 [0.42-0.50]. CmaxGMR [90% CI] for UD-DPI [1.6% blend]/Diskus: 1.20 [1.07-1.33]; UD-DPI [1.6% blend]/MDI: 0.58 [0.52-0.64]). Results were consistent between the 1.6% and the 1.0% blends and systemic exposure for the 3 dose strengths of salbutamol (1.6% blend) showed increases that were 12-16% greater than dose proportional. Systemic exposure due to pulmonary absorption (as calculated from AUC0-12in the presence and absence of charcoal block) was 48% for the UD-DPI, 24% for Diskus, and 37% for MDI of the total salbutamol systemic exposure, and the corresponding estimated lung dose was 65% for the UD-DPI and 34% for the Diskus relative to the MDI.


CONCLUSIONS
Salbutamol total systemic exposure following UD-DPI was similar to that from the Diskus and was lower than that following the MDI. The different blend formulations tested resulted in consistent salbutamol systemic exposure. The contribution of the lung and gut to systemic exposure revealed a different profile for the three inhaler platforms. These data suggest that the UD-DPI warrants further evaluation.
1 GSK , Stockley Park, Uxbridge, United Kingdom .
Alison
A
Moore
2 GSK , Sydney, Australia .
Kylie
K
Riddell
3 Quantitative Sciences India, GSK , Bangalore, India .
Shashidhar
S
Joshi
1 GSK , Stockley Park, Uxbridge, United Kingdom .
Robert
R
Chan
4 GSK, Research Triangle Park , North Carolina.
Rashmi
R
Mehta
D000280:Administration, Inhalation; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D058995:Dry Powder Inhalers; D005079:Excipients / Q000737:chemistry; D005260:Female; D006801:Humans; D007785:Lactose / Q000737:chemistry; D008168:Lung / Q000378:metabolism*; D008297:Male; D036501:Metered Dose Inhalers; D008875:Middle Aged; D014018:Tissue Distribution; D055815:Young Adult
D001993:Bronchodilator Agents; D005079:Excipients; D007785:Lactose; D000420:Albuterol
healthy volunteers; metered dose inhaler; multi-dose dry powder inhaler; pharmacokinetics; unit dose dry powder inhaler