Budesonide is a synthetic corticosteroid having potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-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. In glucocorticoid receptor affinity studies, the 22R form was twice as active as the 22S epimer.
The precise mechanism of corticosteroid actions in seasonal and perennial allergic rhinitis is not 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, and cytokines) involved in allergic mediated inflammation.
Corticosteroids affect the delayed (6 hour) response to an allergen challenge more than the histamine-associated immediate response (20 minute). The clinical significance of these findings is unknown.
The pharmacokinetics of budesonide have been studied following nasal, oral, and intravenous administration. Budesonide is relatively well absorbed after both inhalation and oral administration, and is rapidly metabolized into metabolites with low corticosteroid potency. The clinical activity of RHINOCORT AQUA Nasal Spray is therefore believed to be due to the parent drug, budesonide. In vitro studies indicate that the two epimeric forms of budesonide do not interconvert.
Following intranasal administration of RHINOCORT AQUA, the mean peak plasma concentration occurs at approximately 0.7 hours. Compared to an intravenous dose, approximately 34% of the delivered intranasal dose reaches the systemic circulation, most of which is absorbed through the nasal mucosa. While budesonide is well absorbed from the GI tract, the oral bioavailability of budesonide is low (~10%) primarily due to extensive first pass metabolism in the liver.
Budesonide has a volume of distribution of approximately 2-3 L/kg. The volume of distribution for the 22R epimer is almost twice that of the 22S epimer. Protein binding of budesonide in vitro is constant (85-90%) over a concentration range (1-100 nmol/L) which exceeded that achieved after administration of recommended doses. Budesonide shows little to no binding to glucocorticosteroid binding globulin. It rapidly equilibrates with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.
Budesonide is rapidly and extensively metabolized in humans by the liver. Two major metabolites (16α-hydroxyprednisolone and 6β-hydroxybudesonide) are formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation. Known metabolic inhibitors of CYP3A4 (eg, ketoconazole), or significant hepatic impairment, may increase the systemic exposure of unmetabolized budesonide (see WARNINGS and PRECAUTIONS). In vitro studies on the binding of the two primary metabolites to the glucocorticoid receptor indicate that they have less than 1% of the affinity for the receptor as the parent compound budesonide. In vitro studies have evaluated sites of metabolism and showed negligible metabolism in skin, lung, and serum. No qualitative difference between the in vitro and in vivo metabolic patterns could be detected.
Budesonide is excreted in the urine and feces in the form of metabolites. After intranasal administration of a radiolabeled dose, 2/3 of the radioactivity was found in the urine and the remainder in the feces. The main metabolites of budesonide in the 0-24 hour urine sample following IV administration are 16α-hydroxyprednisolone (24%) and 6β-hydroxybudesonide (5%). An additional 34% of the radioactivity recovered in the urine was identified as conjugates.
The 22R form was preferentially cleared with clearance value of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was similar for both epimers and it appeared to be independent of dose.
Geriatric: No specific pharmacokinetic study has been undertaken in subjects >65 years of age.
Pediatric: After administration of RHINOCORT AQUA Nasal Spray, the time to reach peak drug concentrations and plasma half-life were similar in children and in adults. Children had plasma concentrations approximately twice those observed in adults due primarily to differences in weight between children and adults.
Gender: No specific pharmacokinetic study has been conducted to evaluate the effect of gender on budesonide pharmacokinetics. However, following administration of 400 mcg of RHINOCORT AQUA Nasal Spray to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender differences in the pharmacokinetic parameters were found.
Race: No specific study has been undertaken to evaluate the effect of race on budesonide pharmacokinetics.
Renal Insufficiency: The pharmacokinetics of budesonide have not been investigated in patients with renal insufficiency.
Hepatic Insufficiency: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of orally administered budesonide were affected by compromised liver function as evidenced by a doubled systemic availability. The relevance of this finding to intranasally administered budesonide has not been established.
A 3-week clinical study in seasonal rhinitis, comparing RHINOCORT Nasal Inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of RHINOCORT Nasal Inhaler can be attributed to the topical effects of budesonide.
The effects of RHINOCORT AQUA Nasal Spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily of RHINOCORT AQUA Nasal Spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to 12 months.
After treatment with the recommended maximal daily dose of RHINOCORT AQUA (256 mcg) for seven days, there was a small, but statistically significant decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24h) in healthy adult volunteers.
A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of RHINOCORT AQUA doses ranging from 100-800 mcg daily for up to four days in 78 healthy adult volunteers. The clinical relevance of these results is unknown.
The therapeutic efficacy of RHINOCORT AQUA Nasal Spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration.
The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian.
Overall, the results of these clinical trials showed that RHINOCORT AQUA Nasal Spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion.
An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients which demonstrated that RHINOCORT AQUA Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment.