Pharmacotherapeutic Group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has an approximately 200-fold higher affinity for the glucocorticoid receptor and a 1,000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, cytokines) involved in allergic and nonallergic-mediated inflammation.
The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including budesonide inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first-pass hepatic degradation of orally absorbed drug (85% to 95%), and the low potency of metabolites.
The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1,400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide despite comparable systemic levels. Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks. The effects of budesonide inhalation suspension on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 children, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with budesonide inhalation suspension treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n = 21) receiving a total daily dose of budesonide inhalation suspension equivalent to 0.25 mg (n = 5), 0.5 mg (n = 5), 1 mg (n = 8), or placebo (n = 3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted.
All patients were randomized to receive either 0.5 mg or 1 mg of budesonide inhalation suspension or placebo once daily. A total of 28, 17, and 31 patients in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0.5 mg, 2 of whom received budesonide inhalation suspension 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (greater than or equal to 500 nmol/L) to a subnormal level (less than 500 nmol/L) at week 12. In 4 of these patients receiving budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L.
The effects of budesonide inhalation suspension at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The 2 higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43% to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.
Budesonide inhalation suspension, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods.
Pharmacokinetics: Absorption: After a single dose of 1 mg budesonide, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization in asthmatic children 4 to 6 years of age. The exposure (AUC) of budesonide following administration of a single 1 mg dose of budesonide by nebulization to asthmatic children 4 to 6 years of age is comparable to healthy adults given a single 2 mg dose by nebulization. In asthmatic children 4 to 6 years of age, the total absolute bioavailability (ie, lung + oral) following administration of budesonide inhalation suspension via jet nebulizer was approximately 6% of the labeled dose. The peak plasma concentration of budesonide occurred 10 to 30 minutes after start of nebulization.
Distribution: In asthmatic children 4 to 6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85% to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of approximately 0.8.
Metabolism: In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16-hydroxyprednisolone and 6ß-hydroxybudesonide. The corticosteroid activity of each of these 2 metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. The activity of budesonide is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was 2 times as active as the 22S epimer. In vitro studies indicated that the 2 forms of budesonide do not interconvert.
Budesonide is primarily cleared by the liver. In asthmatic children 4 to 6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight.
Excretion: Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.
Special Populations: Hepatic Function Impairment: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The IV pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults.
Children: Following IV dosing in children age 10 to 14 years, plasma half-life was shorter than in adults (1.5 hours vs 2 hours in adults). In the same population following inhalation of budesonide via a pressurized metered-dose inhaler, absolute systemic availability was similar to that in adults.
No pharmacokinetic differences have been identified due to race, gender, or age.
Toxicology: Preclinical Safety Data: The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.