Abstract

Background: Levalbuterol (LEV), the (R)-enantiomer of racemic albuterol (RA), is approved for the treatment or prevention of bronchospasm in patients ≥4 years of age via metered dose inhaler (MDI). A population pharmacokinetic (PPK) model for (R)-albuterol following inhaled LEV or RA was developed, and the magnitude and variability of systemic exposure in pediatric and adult asthma patients were assessed.

Methods: Data were pooled from 81 pediatric and 551 adult subjects (aged 4-81 years) enrolled in three Phase 3 clinical trials. Plasma drug concentrations (n=3791) obtained following the first dose and after 4 or 8 weeks of QID inhalations (90 μg LEV or 180 μg RA via HFA MDI) were modeled using NONMEM®. Subject covariates were evaluated with stepwise forward selection (α=0.05) and backward elimination (α=0.001).

Results: The PK of (R)-albuterol was described by a 2-compartment model with first-order absorption and elimination. A significant positive relationship was identified between body weight and both apparent clearance (CL/F) and central volume of distribution (Vc/F). Mean (SD) individual predicted CL/F and Vc/F for LEV were 60.6 (15.4) L/hr and 493 (158) L, respectively. No significant differences in (R)-albuterol exposure existed across the age range (4-81 years), although exposure was 13 to 30% lower in subjects receiving LEV compared to RA.

Conclusions: A PPK model describing (R)-albuterol PK in pediatric and adult asthmatics was developed that will enable prediction of (R)-albuterol concentrations for future exposure-response analyses.

American Association of Pharmaceutical Scientists (AAPS), San Antonio, Texas, October 2006

By David Jaworowicz, Maier G, Baumgartner RA, Hsu R, Thaddeus H. Grasela