Quantifying Lung Function Progression in Asthma
Guangli Ma1, Bo L Olsson2, Johan Rosenborg2, Mats O. Karlsson1
1Department of Pharmaceutical Biosciences, Uppsala University, Sweden 2AstraZeneca Ltd, Clinical Pharmacology DMPK, Lund, Sweden
Objectives:Lung function is an important indicator of asthma [1]. Although the relationship between aging and lung function in healthy people has been previously studied [2], lung function progression in asthma has not been similary explored [1]. This study aimed to quantify lung function, expressed as FEV1, progression of asthma and to evaluate short-term and long-term effects after formoterol and terbutaline treatments.
Methods:The FEV1 data set was collected from two randomized, double-blind, multi-centre, parallel designed clinical trials [3] in patients with intermittent asthma and mild persistent asthma. These two trials contained 1130 patients with formoterol or terbutaline treatments with an age range between 6 to 88 years [3].
The equation for healthy subjects [4] was re-estimated to quantify lung function progression in asthma. Drug effects, aging effects, and the difference between intermittent asthma and mild persistent asthma were analyzed in NONMEM. Visual predictive checks (VPCs) were employed for model evaluation.
Results: : The difference in lung function progression between intermittent asthma and mild persistent asthma was not significant. FEV1 in asthma could be quantified by age (AGE), body weight (WT), and height (HT): FEV1 = EXP(0.174*LOG(AGE) + 0.122*LOG(WT) + 0.0168*HT – 0.00141*WT – 0.011*AGE – 2.33. VPCs stratified on age, weight and height revealed that the predictions were in accordance with observations.
Based on the above FEV1 progression function, the drug effects of formoterol and terbutaline, regardless of asthma status (intermittent or mild persistent), were determined to be similar. The acute improvement of lung function after treatments was about 6%. Neither of these two drugs appeared to change long-term lung function progression of asthma.
Conclusions:Lung function progression of asthma was quantified. Formoterol and terbutaline equally improved lung function, but no influence was determined on lung function progression. This study also proposed a population approach to model chronic disease progression from normal clinical trial designs.
References:
[1] Pedersen, S. Am J Respir Crit Care Med; 2004; 170(3): p. 206-207.
[2] Chan, P.L. and N.H. Holford. Annu Rev Pharmacol Toxicol; 2001; 41: p. 625-59.
[3] Chuchalin, A., et al. Respir Med; 2005; 99(4): p. 461-70.
[4] Kristufek, P., et al. Bull Eur Physiopathol Respir; 1987; 23(2): p. 139-47.
