Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Corticosteroids acting locally,
ATC code: A07EA06

The exact mechanism of budesonide in the treatment of inflammatory bowel diseases is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Budeson gastro-resistant granules 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.
Budeson gastro-resistant granules show a dose-dependent influence on cortisol plasma levels which is at the recommended dose of 9mg budesonide/day significantly smaller than that of clinically equivalent effective doses of systemic glucocorticosteroids.

Clinical study in patients with Crohn’s disease
In a randomized, double-blind, double-dummy trial in patients with mild to moderate Crohn’s disease (200 < CDAI < 400) affecting the terminal ileum and/or the ascending colon the efficacy of 9mg budesonide in a single daily dose (9mg OD) was compared to the treatment with 3mg budesonide given three times daily (3mg TID).
The primary efficacy endpoint was the proportion of patients in remission (CDAI<150) at week 8.

A total of 471 patients were included in the study (full analysis set, FAS), 439 patients were in the per protocol (PP) analysis set. There were no relevant differences in the baseline characteristics in both treatment groups. At the confirmatory analysis, 71.3% of the patients were in remission in the 9mg OD group and 75.1% in the 3mg TID group (PP) (p = 0.01975) demonstrating the non-inferiority of 9mg budesonide OD to 3mg budesonide TID.

No drug-related serious adverse events were reported.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Due to the specific coating of the Budeson gastro-resistant granules there is a lag phase of 2-3 hours. In fasting healthy volunteers, mean peak plasma concentrations of budesonide were 2.2 ng/mL at about 6 hours following a single oral dose of 9mg budesonide gastro- resistant granules.

In a study with a single dose of budesonide 3mg gastro-resistant granules it was shown that concomitant intake of food may delay release of granules from stomach by about 2-3 hours, prolonging the lag phase to about 4-6 hours, without change in absorption rates.

Distribution
Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding is, on average, 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 16-hydroxyprednisolone, is less than 1% of that of budesonide.

Elimination
The average elimination half-life is about 3-4 hours. The systemic availability in healthy volunteers as well as in fasting patients with inflammatory bowel diseases is about 9-13 %. Clearance of budesonide is about 10-15 L/min.
Budesonide is eliminated only in marginal, if any, amounts by the kidney.

Specific patient populations (liver diseases)
A relevant proportion of budesonide is metabolised in the liver. The systemic exposure of budesonide might be increased in patients with impaired hepatic function due to a decrease in budesonide metabolism by CYP3A4. This is dependent on the type and severity of liver disease.