Pharmacotherapeutic Group: Intestinal anti-inflammatory agents; Corticosteroids acting locally. ATC Code: A07E A06.
Pharmacology: Pharmacodynamics: Mechanism of Action: The exact mechanism of action of budesonide in the treatment of UC is not fully understood. In general, budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.
Data from clinical pharmacology and pharmacokinetic studies indicate that the mode of action of CORTIMENT tablets is based on a local action in the gut.
Pharmacodynamic effects: MMX extended release technology is characterised by a multi-matrix structure covered by a gastro-resistant coating that dissolves in intestinal fluids having a pH greater than 7.
When the dosage form is administered, the gastro-protective layer protects the dosage form during transit through the stomach and duodenum up to the lower part of the intestine. When the protective layer is lost the intestinal fluid then comes into contact with the hydrophilic matrix polymers, which start to swell until a viscous gel matrix is formed. The solvent that penetrates into the gel matrix dissolves the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate throughout the colon.
Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a topical anti-inflammatory activity, but does not reduce cortisol levels to the same extent as systemic glucocorticoids.
Clinical efficacy: Two randomised, controlled phase III clinical trials including 1022 patients with mild to moderate active UC have been performed in adult patients. Two hundred fifty five (255) patients were treated for 8 weeks with CORTIMENT 9 mg per day. Patients included were either treatment naïve (42% ITT) or had failed on 5-ASA (58% ITT). Both studies included a reference arm, mesalazine (Asacol) and budesonide (Entocort), respectively to show assay sensitivity. The definition of remission applied in both studies was UCDAI score of ≤1, with 0 score for rectal bleeding and stool frequency, normal mucosa (no friability) and ≥1 point reduction in endoscopy score. (See Table 1.)
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Statistical difference versus placebo was reached for CORTIMENT 9 mg for both studies and the difference versus placebo was 10.4% and 12.9% respectively.
5-ASA is the Standard of Care for treatment of mild to moderate disease. Results of a head to head comparison with CORTIMENT and 5-ASA were not available. Therefore, the place in the therapeutic work-up remains to be established. Some patients may benefit from treatment initially with CORTIMENT.
Paediatric Population: CORTIMENT was not studied in the paediatric population.
Pharmacokinetics: Absorption: After oral dosing of plain micronised compound, absorption seems to be complete. A large proportion of the unformulated drug is absorbed from the ileum and ascending colon.
Systemic availability of Budesonide following a single administration of CORTIMENT tablets in healthy volunteers was compared to that of Entocort and the result was similar, about 10%, due to first pass metabolism in the liver. Maximum plasma concentrations of budesonide are approximately 1.3-1.8 ng/ml at 13-14 hours post administration. Concomitant administration of CORTIMENT tablets with food had no clinically relevant effect on absorption. It has been shown that there is no potential for drug accumulation on repeated dosing.
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 to metabolites of low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination: Elimination of budesonide is rate limited by absorption. Budesonide has a high systemic clearance (about 1.2 L/min).
Paediatric Population: No data or experience is available with respect to the pharmacokinetics of CORTIMENT tablets in the paediatric population.
Toxicology: Preclinical Safety Data: A preclinical toxicology and toxicokinetic bridging study, comparing CORTIMENT tablets with an existing prolonged release budesonide formulation (Entocort EC 3 mg capsules, AstraZeneca) in cynomolgous monkeys has confirmed that CORTIMENT tablets result in a delayed peak exposure and reduced total exposure compared to the existing formulation of budesonide, while maintaining a superimposable toxicological profile.
Preclinical data have shown that budesonide produces effects less severe or similar to other glucocorticoids, such as weight increase, atrophy of the adrenal glands and thymus and effects on the leucocyte count. As with other glucocorticosteroids, and dependent on the dose and duration and the diseases concerned, these steroid effects may also be relevant in man.
Budesonide had no effect on fertility in rats. In pregnant rats and rabbits, budesonide, like other glucocorticosteroids, has been shown to cause foetal death and abnormalities of foetal development (smaller litter size, intrauterine foetal growth retardation and skeletal abnormalities). Some glucocorticoids have been reported to produce cleft palate in animals. The relevance of these findings to man has not been established (see also Use in Pregnancy & Lactation).
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 (in female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from rat studies with other glucocorticosteroids and therefore represent a class effect in this species.