Budenofalk Rectal Foam Mechanism of Action

Pharmacotherapeutic group: Intestinal anti-inflammatory agent. ATC code: A07EA06, Corticosteroid with local effect.
Pharmacology: Pharmacodynamics: The exact mechanism of action of budesonide in the treatment of ulcerative colitis/proctosigmoiditis is not fully understood. Data from clinical pharmacology and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At a dosage of 2 mg budesonide, applied rectally, which is clinically equieffective with systemically acting glucocorticoids, budesonide leads to practically no suppression of the HPA axis. Budenofalk rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.
Pharmacokinetics: General aspects of budesonide: Absorption: After oral application, the systemic availability of budesonide is about 10%.
Distribution: Budesonide has a high volume of distribution (about 3 l/kg). Plasma protein binding averages 85-90%.
Biotransformation: Budesonide undergoes extensive biotransformation in the liver (approximately 90%) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone - both of which are formed via CYP3A - is less than 1% of that of budesonide.
Elimination: The average elimination half-life after oral administration is about 3-4 hours. The mean clearance rate is about 10 l/min for budesonide.
Special patient groups (patients with impaired hepatic function): Depending on the type and severity of the liver disease, the metabolism of budesonide via CYP3A can be reduced in these patients.
Specific aspects of Budenofalk rectal foam: Absorption: The areas under the concentration-time curves after rectal administration are somewhat higher than after oral administration (historical controls). Peak levels with application of Budenofalk rectal foam are obtained after an average of 2-3 hours. Accumulation after repeated application can be ruled out.
Spread: A scintigraphic investigation with technetium-marked Budenofalk rectal foam in patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.
Toxicology: Preclinical safety data: After repeated oral administration of budesonide in rats (dose comparable to that used in humans), a reduction in the leukocyte count (especially lymphocytes) and regression of the thymus gland were observed. There was evidence of adrenal atrophy due to inactivity. Increased lactiferous duct proliferation and secretory activity were found in the mammary glands. In a long-term study (104 weeks), the haematocrit, haemoglobin and red cell count were reduced in female rats. In the same dosage group, there was a tendency for the neutrophil count to increase and values for lymphocytes, eosinophils and normocytes to decrease. The number of lymphocytes was significantly reduced (immunosuppressant effect) and alkaline phosphatase was slightly increased only in male animals.
In dogs, packed cell volume was reduced, alkaline phosphatase and alanine aminotransferase were elevated, the adrenals and lymphatic system were atrophied, and myocardial fat count and hepatic glycogen content (hepatomegaly) were increased.
Mutagenicity: Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.
Carcinogenicity: Male rats treated with budesonide for up to 104 weeks developed a slightly increased number of basophilic hepatic foci compared with control animals. In the carcinogenicity study, the incidences of primary hepatocellular neoplasms (0.025 and 0.05 mg/kg body weight/day), astrocytomas (male rats 0.05 mg/kg body weight/day) and mammary tumours (female rats 0.05 mg/kg body weight/day) were significantly increased. The hepatic tumours are probably due anabolic effects and the increased metabolic load on the liver. The findings represent a class effect probably involving glucocorticoid receptors.
Reproductive toxicity: Glucocorticoids induce teratogenic effects (cleft palate, skeletal malformations) in animal studies in several species. The clinical relevance of these properties is not yet known. In rodents, subcutaneous budesonide showed the changes already known from other glucocorticoids. Animal studies have also shown that administration of synthetic glucocorticoids during gestation can lead to a higher risk of intrauterine growth retardation and can contribute to cardiovascular and/or metabolic diseases in adults, as well as a permanent change in glucocorticoid receptor density, neurotransmitter turnover and behaviour.