Exposure-Response Relationship for Nebulized Arformoterol in Subjects with COPD

Authors: Maier G, Kharidia J, Hanrahan JP, Hsu R, Jaworowicz DJ, Cirincione B, Owen JS, Grasela TH
Conference: ERSC
Keywords: biophase, bronchodilator, chronic obstructive pulmonary disease, Emax, FEV, forced expiratory volume, formoterol, hypothetical compartment, hysteresis, inhaled, link model, NONMEM, PK/PD, pulmonology, respiratory agents, SAS, steady state, time lag
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Abstract

Aim: Arformoterol (ARF) is a highly selective, potent, long-acting β2-adrenoceptor agonist under development in the US for the maintenance treatment of bronchoconstriction associated with COPD. An initial population pharmacokinetic/pharmacodynamic (PK/PD) model described the relationship between the % change in FEV1 (%ΔFEV1) and (R,R)-formoterol plasma concentrations (Cp), and the variability in key PD parameters.

Methods: Data were obtained from one Phase 2 and two Phase 3 studies of nebulized ARF tartrate inhalation solution in COPD subjects, with doses ranging from 5μg BID to 50μg QD. Individual predicted ARF Cp were obtained from Bayesian parameter estimates derived from a previous population PK model. Biophase distribution PK/PD link models were evaluated, as the hysteresis in the plot of %ΔFEV1 vs. ARF Cp suggested a time delay.

Results: A total of 13,294 FEV1 observations obtained after single-dose (SD) and steady-state (SS) dosing of ARF in 501 subjects were evaluated. An Emax (maximum drug response) link model best described the relationship between ARF Cp and %ΔFEV1, with separate residual variability (RV) for Phase 2 and 3 data. Following SD ARF, the Emax was 38 %ΔFEV1 from study baseline, with a relatively small EC50 (concentration at 50% of Emax) of 0.61 pg/mL. The Emax at SS was 55 %ΔFEV1, with an EC50 of 5.23 pg/mL. The estimated first-order distribution rate constant (keo) was 1.49 hr-1 [0.47 hr half-life (t1/2)] for SD and 3.78 hr-1 (0.18 hr t1/2) for SS, which was consistent with the hysteresis plots. Model parameters were well estimated (%SEM ≤ 21%).

Conclusions: The developed PK/PD model demonstrated that a clear exposure-response relationship exists between Cp and FEV1 response after nebulized ARF, and accounts for the small lag time between the time course of drug exposure and drug response observed in the studies.

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