Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agents, ATC code: A07EC02.
Mechanism of action
Asacol contains mesalazine, also known as 5-aminosalicylic acid, which has a topical anti-inflammatory effect on the colonic mucosal cells through mechanisms that have not yet been fully clarified.
Asacol has been shown to inhibit LTB4-stimulated migration of intestinal macrophages by restricting migration of macrophages to inflamed areas. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall is thereby inhibited. Asacol has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.
Pharmacodynamic effects
The Asacol tablet contains a core of 1600 mg mesalazine covered by a multi- layer coating system. This system consists of a layer of methacrylic acid - methyl methacrylate copolymer (Eudragit S) combined with starch particles on top of a middle alkaline buffer layer (which accelerates drug release). The coating is designed to delay release of mesalazine until intestinal fluids reach a pH of 7. The starch can be digested by colonic bacteria which also provides a second trigger for release of mesalazine from the coated tablet. Systemic bioavailability/plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a criterion for safety.
The risk of colorectal cancer (CRC) is slightly elevated in ulcerative colitis.
The effects observed by mesalazine in experimental models and from patient biopsies supports that mesalazine prevents colitis-associated CRC through down regulation of both the inflammation-dependent and non-dependent inflammatory signalling pathways that are involved in the development of colitis-associated CRC. Data from meta-analyses with populations both in remission and relapsing, provide however, an inconsistent clinical information on risk-benefit of mesalazine in the carcinogenesis of ulcerative colitis.
Clinical efficacy and safety
Mild to moderate acute ulcerative colitis
This indication was investigated in a randomised, active-controlled, double- blind, multi-centre, non-inferiority induction trial study with 817 patients receiving 3.2 g mesalazine daily for 8 weeks.
At week 8, 22.4% of the Per-Protocol patients treated with Asacol 1600 mg modified-release tablets and 24.6% of those treated with mesalazine 400 mg tablets achieved clinical and endoscopic remission. The unadjusted between group difference was 2.2% (95% confidence interval: - 8.1% up to 3.8%).
Taking into account the predefined non-inferiority margin of – 10%, once daily Asacol 1600 mg modified-release tablets were considered to be non- inferior to twice daily mesalazine 400 mg tablets in inducing clinical and endoscopic remission.
A total of 10.3% of patients treated with Asacol 1600 mg modified-release tablets and 9.8% of patients receiving mesalazine 400 mg tablets reported treatment related adverse events. The incidence of serious adverse events (SAEs) in both treatment groups was 2.0% versus 1.7%.
Maintenance
727 patients participated in an open label extension (OLE) of the induction study. A total of 243 patients who showed no response at week 8 entered an extended induction period of 8 weeks on a daily dose of 4.8g.
The daily dose of Asacol in the maintenance phase was allocated depending on the 8 or 12-week induction results. Patients in clinical remission (202) received 1.6g/day whereas patients with a clinical response (274) received 3.2 g/day. Initial non-responders at week 8 who responded after a further 8 weeks on 4.8 g Asacol per day (199), remained on 4.8 g for another       22 weeks.
At week 38 70.3% (142/202) with 1.6 g/day maintained remission.
Additionally 33.9% (93/274) and 30.7% (61/199) of patients in the 3.2 g/day and 4.8 g/day dose groups, respectively achieved a later clinical remission.
The incidence of SAEs in the maintenance OLE was low and independent of daily dose, with 5.0% (10/202), 4.4% (12/274) and 1.5% (3/199) of patients in the 1.6, 3.2 and 4.8 g/day dose groups affected.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
Absorption
Asacol tablets have a modified release of mesalazine starting only at pH above 7, i.e. within the terminal ileum and colon. Approximately 31% of an oral dose (fasted state) is absorbed based on urinary excretion data for 60 hours.
A single dose of a Asacol 1600 mg modified -release tablets in healthy volunteers in the fasted state resulted in a 1.5-fold increase of mesalazine Cmax and a 1.5-fold increase of AUC compared to fed state.
Distribution
About 43% mesalazine and 78% N-acetyl mesalazine are bound to plasma proteins.
Approximately 75 % of the administered dose remains in the gut lumen and the mucosal tissue. The mean apparent volume of distribution (Vdw) was 12.1 l/kg. Low concentrations of mesalazine and N-acetyl mesalazine have been detected in human breast milk. The clinical significance of this has not been determined.
Biotransformation
Mesalazine is metabolised both by the intestinal mucosa and the liver to the inactive metabolite N-acetyl mesalazine. Based on urinary excretion data, the absorbed dose is excreted to >95% as metabolites.
Elimination
The elimination of mesalazine is essentially urinary and faecal in the form of mesalazine and its N-acetyl metabolite. About 23% of the dose administered was recovered in the urine within 60 hours after fed and 31% under fasted administration (single dose of 1600 mg tablet). The median elimination half- life of mesalazine was 20 hours (range: 5 to 77 hours).