Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Aminosalicylic acid and similar agents
ATC code: A07EC02
The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.
Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-Aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.
On reaching the intestinal lumen, rectally administered mesalazine has largely local effects on the intestinal mucosa and submucosal tissue.

Clinical efficacy and safety of mesalazine 1 g suppositories was evaluated in a multicentre phase III study, which included 403 patients with endoscopically and histologically confirmed mild to moderately active ulcerative proctitis. The mean disease activity index (DAI) at base line was 6.2 ± 1.5 (range: 3 – 10). Patients were randomised to treatment with one mesalazine 1 g suppository (1 g OD group) or 3 suppositories containing 0.5 g mesalazine (0.5 g TID group per day for 6 weeks. The primary efficacy variable was clinical remission defined as DAI < 4 at the final visit or withdrawal. At the final per protocol analysis, 87.9% of the patients in the 1 g OD group and 90.7% of the 0.5 g TID group were in clinical remission (Intention-to-treat analysis: 1 g OD group: 84.0%; 0.5 g TID group: 84.7%).
The mean change in DAI from baseline was -4.7 in both treatment groups. No drug-related serious AEs occurred.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
General considerations of mesalazine:

Absorption:
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.

Biotransformation:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and in the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.

Elimination:
Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50 %, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA. About 1 % of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.

Mesalazine 1g suppositories specific:
Distribution:
Scintigraphic studies with a similar medicinal product, technetium-labelled mesalazine 500mg suppositories showed peak spread of the suppository that had melted due to body temperature after 2 – 3 hours. The spread was limited primarily to the rectum and rectosigmoid junction. It is assumed that mesalazine 1g suppositories act very similar and thus are particularly suitable for treating proctitis (ulcerative colitis of the rectum).
Absorption:
In healthy subjects mean peak plasma concentrations of 5-ASA after a single rectal dose of 1g mesalazine (mesalazine 1 g Suppository) were 192 ± 125 ng/ml (range 19 –557 ng/ml), those of the main metabolite N-Ac-5-ASA were 402 ± 211 ng/ml (range 57 – 1070 ng/ml). Time to reach the peak plasma concentration of 5-ASA was 7.1 ±4.9 h (range 0.3 – 24 h).
Elimination:
In healthy subjects, after a single rectal dose of 1g mesalazine (mesalazine 1g Suppository) approx. 14 % of the administered 5-ASA dose were recovered in the urine during 48 hours.