Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma

PURPOSE: Inhaled corticosteroids have beneficial effects on pulmonary funct ion and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their d ose-response effects on lung function, surrogate markers of airway inflamma tion, and tests of adrenal function. SUBJECTS AND METHODS: After a 10-day placebo run-in, we evaluated the effec ts of 200 mu g, 400 mu g, and 800 mu g of inhaled budesonide, each dose giv en twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 year s (mean +/- SD), with mild-to-moderate asthma. Measurements were made of br onchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 hbn and after stimulation with human corticotropin releasing factor. RESULTS: For measurements of pulmonary function and exhaled nitric oxide, t here was a plateau in the mean response to budesonide between 400 mu g (low dose) and 800 mu g (medium dose) per day, whereas for eosinophilic cationi c protein and bronchial challenge, maximal benefits occurred between 800 an d 1,600 mu g (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 mu g of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway respo nse (fourfold decrease in bronchial hyperreactivity) and minimal systemic r esponse (overnight urinary cortisol greater than 20 nmol), was similar at l ow-dose (46%) and at high-dose (52%) budesonide. The pro; portion of patien ts with a suboptimal therapeutic index, a good airway response with a marke d systemic response (overnight urinary cortisol greater than 20 nmol), incr eased from 4% at low dose to 38% at high dose. CONCLUSIONS: In patients with mild-to-moderate atopic asthma, there were do se-related effects of budesonide on surrogate markers of inflammation (bron chial hyperreactivity and serum eosinophilic cationic protein), although hi gher doses were associated with adrenal suppression and a decrease in the t herapeutic index. Am J Med. 2000;108:269-275. (C) 2000 by Excerpta Medica, Inc.