Chemical formula: C₂₅H₃₄O₆ Molecular mass: 430.534 g/mol PubChem compound: 5281004
The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Antiinflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of budesonide, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone.
The exact mechanism of budesonide in the treatment of Crohn’s disease is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of budesonide capsules is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to systemically acting glucocorticosteroids, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
Budesonide show a dose-dependent influence on cortisol plasma levels which is at the recommended dose of 9 mg budesonide/day significantly smaller than that of clinically equivalent effective doses of systemic glucocorticosteroids.
It is used intranasally for the prophylaxis and treatment of allergic rhinitis. Intranasal corticosteroids are quickly metabolised to less active metabolites, are minimally absorbed, and have been associated with few systemic adverse effects. Studies have shown that control of allergic rhinitis symptoms by intra-nasal 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.
Budesonide capsules, which contain gastric juice resistant granules, have – due to the specific coating of the granules – a lag phase of 2-3 hours. In healthy volunteers, as well as in patients with Crohn’s disease, mean maximal budesonide plasma concentrations of 1-2 ng/ml were seen at about 5 hours following an oral dose of budesonide capsules at a single dose of 3 mg, taken before meals. The maximal release therefore occurs in the terminal ileum and caecum, the main area of inflammation in Crohn’s disease.
In ileostomy patients release of budesonide from capsules is comparable to healthy subjects or Crohn’s disease patients. In ileostomy patients it was demonstrated that about 30–40% of released budesonide is still found in the ileostomy bag, indicating that a substantial amount of budesonide from capsules will be transferred normally into the colon.
Concomitant intake of food may delay release of granules from stomach by 2-3 hours, prolonging the lag phase to about 4-6 hours, without change in absorption rates.
In adults the systemic availability of budesonide following administration of nebuliser suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
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%. The systemic availability of budesonide from this medicine, with reference to the metered dose is 33%. In adults, the maximal plasma concentration after administration of 256 micrograms budesonide from this medicine is 0.64 nM and is reached within 0.7 hours. The AUC after administration of 256 micrograms budesonide from this medicine is 2.7 nmolxh/L in adults.
After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2-3 hours after administering Budenofalk 2mg rectal foam.
Budesonide has a high volume of distribution (about 3 l/kg). Plasma protein binding averages between 85 and 90%.
The epimers of budesonide have large volumes of distribution – 424 L 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.
Budesonide undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Budesonide is excreted primarily as metabolites in the urine and faeces. 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.
The systemic availability in healthy volunteers as well as in fasting patients with Crohn’s disease is about 9-13%. The clearance rate is about 10-15 l/min for budesonide, determined by HPLC-based methods.
The kinetics of budesonide are dose-proportional at clinically relevant doses.
Paediatric population Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of budesonide following administration of Budesonide Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus with Pari Master compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
A scintigraphic investigation with technetium-marked budesonide rectal foam on patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.
A relevant proportion of budesonide is metabolised in the liver. The systemic exposure of budesonide might be increased in patients with impaired hepatic functions due to a decrease in budesonide metabolism by CYP3A4. This is dependent on the type and severity of liver disease.
There are no budesonide pharmacokinetic data available in elderly patients.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of budesonide following administration of nebuliser suspension via a jet nebuliser is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
Pharmacokinetics of budesonide were evaluated in 12 paediatric patients with Crohn’s disease (age: 5 to 15 years). Following multiple dose administration of budesonide (3 × 3 mg of budesonide for one week) mean AUC of budesonide during the dosing interval was about 7 ng h/ml, and Cmax about 2 ng/ml. Disposition of oral budesonide (3 mg, single dose) in paediatric patients was similar to that in adults.
Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. Like with other glucocorticosteroids, and in dependence of the dose and duration and in dependence of the diseases these steroid effects might also be of relevance in man.
Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.
A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide and in carcinogenicity studies an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.
In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However these animal experimental results do not appear to be relevant in humans at the recommended doses.
Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.
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