Abstract

Aim: (R,R)-Formoterol (ARF) is a highly selective, potent and long-acting β2-adrenoceptor agonist currently under development in the US for the longterm maintenance treatment of bronchoconstriction associated with COPD. The objectives of this analysis were to develop a population pharmacokinetic (PPK) model for nebulized ARF, and define the magnitude and variability of systemic exposure in subjects with COPD.

Methods: Data were pooled from one Phase 2 and two Phase 3 studies evaluating nebulized ARF tartrate inhalation solution administered at doses ranging from 5 μg BID to 50 μg QD. Both 1- and 2-compartment (CMT) models were evaluated using NONMEM®. Subject covariates were evaluated using stepwise forward (α = 0.05) and backward (α = 0.001) selection.

Results: A total of 6,401 ARF plasma concentrations were available from 503 subjects. A 2-CMT model with first-order absorption and elimination best described the data. Weight was a significant predictor of central volume of distribution (Vc/F), total body clearance (CL/F), and intercompartmental clearance (Q), where body weight was positively associated with increases in these parameter values. Mean (SD) Bayesian estimates of the area under the concentration-time curve (AUC) suggested dose-proportionality over this range. Measures of the precision and accuracy were unbiased, with a mean individual prediction error of 1.9%.

Conclusions: A PPK model was developed for nebulized ARF, and thus provides a valid and unbiased tool for estimating AUC in support of future exposure-response analyses.

European Respiratory Society Congress (ERSC), Munich, Germany, September 2006

By G Maier, J Kharidia, JP Hanrahan, R Hsu, David Jaworowicz, B Cirincione, Joel S. Owen, Thaddeus H. Grasela