Exposure-Response and Clinical Outcome Modeling of Inhaled Budesonide/Formoterol Combination in Asthma Patients

Abstract

Exposure-response and clinical outcome (CO) model for inhaled budesonide/formoterol was developed to quantify the relationship among pharmacokinetics (PK), pharmacodynamics (PD) and CO of the drugs and evaluate the covariate effect on model parameters. Sputum eosinophils cationic proteins (ECP) and forced expiratory volume (FEV1) were selected as PD markers and asthma control score was used as a clinical outcome. One-and two-compartment models were used to describe the PK of budesonide and formoterol, respectively. The indirect response model (IDR) was used to describe the PD effect for ECP and FEV1. In addition, the symptomatic effect on the disease progression model for CO was connected with IDR on each PD response. The slope for the effect of ECP and FEV1 to disease progression were estimated as 0.00008 and 0.644, respectively. Total five covariates (ex. ADRB2 genotype etc.) were searched using a stepwise covariate modeling method, however, there was no significant covariate effect. The results from the simulation study were showed that a 1 puff b.i.d. had a comparable effect of asthma control with a 2 puff b.i.d. As a result, the 1 puff b.i.d. of combination drug could be suggested as a standardized dose to minimize the side effects and obtain desired control of disease compared to the 2 puff b.i.d.Pharmaceutics 2020, 12, 336 2 of 16 asthma have been steadily rising, with the patients' burden increasing by around 30% over the past two decades [2][3][4]. It is a complex disease that can be caused by various factors including genetic backgrounds, and has numerous risk factors such as allergens and irritants from the surrounding environment [4]. The rise in prevalence has been related to the recent changes in the lifestyle, which increases exposure to the environmental triggers and it has become a disease that affects almost all populations worldwide [2].Due to the heterogeneity in the clinical and mechanistic characteristics of asthma, efficient prevention and treatment strategies have proven to be challenging to develop [4,5]. A combination of corticosteroids and β 2 -adrenergic agonists are commonly used to relieve the symptoms of the disease (such as, dyspnea, and bronchospasm) [2,6]. Inhaled corticosteroids can suppress the inflammatory reactions, thereby alleviating levels of eosinophils and other inflammatory factors including eosinophils cationic proteins (ECP), which is one of the major inflammatory biomarkers in asthma [4,[6][7][8]. Obstruction of the airways can be relieved and pulmonary function can be increased after inhalation of β 2 -adrenergic agonists, which constrict the smooth muscles of the bronchi. Short-acting β 2 -adrenergic agonists (SABA) are commonly used for a quick relief of acute symptoms, and long-acting β 2 -adrenergic agonists (LABA) are mainly for long-term control of the disease [4,6,9] During the past decade, the management strategies of asthma have seen a gradual change from alleviating acute symptoms to achieving a more constant control of the disease [10]. According to the G...

The anti-inflammatory effects of inhaled steroids and β2-agonist added to inhaled steroids in the treatment of mild asthma

“…Combination medication may be recommended as a standard dose to minimize side effects and achieve desired control of disease compared to 2 puffs b.i.d. [28].…”