Pharmacology: Pharmacodynamics: Budesonide is a corticosteroid with mainly glucocorticoid activity. It is used intranasally for the prophylaxis and treatment of allergic rhinitis. Corticosteroids are generally considered the most effective medications for the management of inflammatory diseases. Intranasal corticosteroids are quickly metabolized to less active metabolites, minimally absorbed, and have been associated with few systemic adverse effects. Studies have shown that control of allergic rhinitis symptoms by intranasal corticosteroids is dependent on local activity.
Glucocorticoid potency is closely related to their glucocorticoid receptor (GR) binding affinity within the target cell. This receptor binding triggers a cascade of biochemical reactions within the target cell, thereby affecting the rate of protein synthesis. This is responsible for the anti-inflammatory effect of glucocorticoids. Upon GR activation, there is a decrease in the production of cytokines and other inflammatory mediators such as kinins, histamine, and platelet activating factor. Corticosteroids also reduce the number of circulating T lymphocytes and inhibit activation of other T lymphocytes. The inhibition of T lymphocytes and cytokine production reduce the recruitment and influx of circulating eosinophils, macrophages, and basophils into the nasal epithelium.
Pharmacokinetics: Absorption: Budesonide is moderately lipophilic and systemic exposure is primarily due to its rapid absorption through the nasal mucosa. The systemic bioavailability of budesonide following intranasal administration is 6 to 16% while its pulmonary bioavailability is 28%.
Metered doses of budesonide 400 mcg to 1600 mcg given as single or repeated doses reach peak plasma concentrations of 0.51 nmol/L to 5.37 nmol/L and 2.03 nmol/L to 6.40 nmol/L, respectively. No consistent differences in the peak plasma concentrations between the epimers of budesonide, 22R and 22S, have been reported.
Following inhalation, the mean time to peak plasma concentration of budesonide is achieved within 1 to 2 hours.
Distribution: Budesonide is distributed widely into tissues with plasma protein binding averaging between 85 and 90%. The epimers of budesonide have large volumes of distribution - 424L for 22R-budesonide and 245 L for 22S-budesonide. 22R-budesonide has a larger volume of distribution than the 22S epimer due to its greater lipophilicity. At steady state, the active, unbound form of budesonide has a volume of distribution of approximately 3 L/kg in both adults and children.
Metabolism: Although budesonide is rapidly and extensively absorbed through the lungs, it is not biotransformed in the lung or gastrointestinal tract. Budesonide is metabolized in the liver primarily via oxidative and reductive pathways. Budesonide undergoes an extensive degree (~90%) of biotransformation on first passage by CYP3A4 enzymes to metabolites of low glucocorticosteroid activity. Major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, have similar half-lives but are relatively inactive compared to budesonide having less than 1% of its glucocorticoid and anti-inflammatory activity.
Elimination: Budesonide is excreted primarily as metabolites in the urine and feces. No intact budesonide has been detected in the urine. Budesonide systemic clearance is 0.92 to 1.4 L/min. The half-life of unchanged budesonide following both inhalation and intravenous administration averages between 2 to 4 hours.
Special Population: Pediatrics: The bioavailability of budesonide in children with asthma is reported to be 25.4±10.4% for the 22R epimer and 29.6±12.4% for the 22S epimer after inhalation of the nominal dose. Total systemic availability in 3- to 6-year old children is approximately 6% of the labeled dose and a peak plasma concentration of 2.6 nmol/L is achieved within 10 to 30 minutes after inhalation. The volume of distribution in children with asthma is reported at 3.11 kg/L and 4.8 kg/L for the 22R and 22S epimer of budesonide, respectively. At steady state, the volume of distribution has been reported to be 55 L when administered via nebulization. Systemic clearance is approximately 50% higher than in healthy adults. Total plasma clearance is higher for the 22R epimer than for the 22S epimer (2.0 L/kg·h versus 1.51 L/kg·h, P<0.001) while terminal elimination half-life is 2.3 hours.
Elderly: There are no budesonide pharmacokinetic data available in elderly patients.
Toxicology: Pre-Clinical Safety Data: Summary: Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenicity and toxicity to reproduction and development.