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 an anti- inflammatory effect through a mechanism that has not yet been fully clarified.
Mesalazine has been shown to inhibit LTB4-stimulated migration of intestinal macrophages and thus may reduce intestinal inflammation 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 inhibited. Mesalazine has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.

Pharmacodynamic effects
Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear.
Mesalazine inhibits the formation of platelet activating factor (PAF). Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals.

Clinical efficacy and safety
Mild to moderate acute ulcerative colitis
Asacol 800 mg Tablets have been evaluated in 140 patients with mild to moderate active ulcerative colitis in one controlled study lasting for 10 weeks comparing safety and efficacy versus placebo. This indication was also investigated in seven controlled and three open clinical trials including 787 patients, of whom 559 received Asacol 400 mg Modified Release Tablets. Three studies were placebo-controlled, one of which also compared the efficacy of Asacol to another proprietary oral mesalazine product.
Five studies were performed without comparator. The studies included dose ranging of Asacol. One study compared the efficacy of mesalazine versus sulfasalazine. The studies included dose ranging of Asacol from 1.2 g/day to 4.8 g/day. One study used computerised morphometry to assess the efficacy of Asacol compared with a prednisolone enema. These studies established the safety and efficacy of Asacol for the treatment of mild to moderate acute UC at daily doses of 2.4 – 4.8 g mesalazine.


Maintenance of remission of ulcerative colitis
The efficacy of Asacol 400 was investigated in a double-blind randomised placebo- controlled study including 264 patients. Treatment success in the two Asacol 400 groups (0.8 g/day and 1.6 g/day) was compared by endoscopic evaluation at the 6- month endpoint with the placebo group by using the Fischer exact test. In the intention- to-treat analysis of all patients, 42 of 87 patients (48.3%) in the placebo group had treatment success compared to 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in the group receiving 0.8 g/day (P= 0.050) and 61 of the 87 patients (70.1% [CI, 59.9% to 80.3%]) in the group receiving 1.6 g/day (P= 0.005). Asacol 400 mg GR Tablets were safe and effective in maintaining remission in quiescent ulcerative colitis.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
Asacol tablets are coated with a pH responsive polymer which enables the release of mesalazine only at a pH above 7, i.e. within the terminal ileum and colon, which are the main sites of inflammation in IBD. After any initial disruption of the coating mesalazine will continue to be released irrespective of the pH. Asacol tablets have been designed to minimise absorption in the digestive tract.

After a single dose of 2.4 g of mesalazine (6 Asacol 400 mg enteric coated Tablets) in healthy volunteers under fasting conditions quantifiable amounts (> 2.00 ng/mL) of mesalazine were observed in plasma after 4.5 h (median tlag). The geometric mean Cmax –value of mesalazine was 722.11 ng/mL with a median tmax of about 9.5 h, whereas that of N-acetyl mesalazine was 1437.90 ng/mL with a median tmax of 12.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after fasted oral administration approximately 25% of the dose (more than 95 % as metabolite) was excreted renally within 60 h.
Following concomitant food intake in the same study a single dose of 2.4 g of mesalazine resulted in quantifiable amounts of mesalazine after 9.0 h (median t lag).
The geometric mean Cmax –value of mesalazine was 1725.93 ng/mL with a median tmax of about 22.0 h, whereas that of N-acetyl mesalazine was 2235.32 ng/mL with a median tmax of 24.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after fed oral administration approximately 30% of the dose (about 90 % as metabolite) was excreted renally within 60 h.
Following concomitant food intake the Cmax-values of mesalazine increased 2.39-fold, and the extent of exposure (AUC0-tlast) increased 1.57-fold. Concerning N-acetyl mesalazine after concomitant food intake the Cmax-values increased 1.55-fold, whereas its extent of exposure increased about 1.1-fold only.

Distribution
About 43% mesalazine and about 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 per kg of body weight (Vdw) was 59.07 L/kg (geometric mean: 48.86 L/kg) after a single dose of 2.40 g of mesalazine (6 enteric coated tablets of Asacol 400 mg) in healthy volunteers under fasting conditions. Based upon the absorption of 24.8% of the administered dose, this parameter is equal to 14.65 L/kg (geometric mean: 12.12 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. At least 90% of the drug recovered in the urine after oral administration is found as the main metabolite N-acetyl-mesalazine.

Elimination
The elimination of mesalazine is essentially urinary and faecal in the form of mesalazine and its N-acetyl metabolite. The geometric mean of total apparent clearance of mesalazine after administration of 2.40 g of mesalazine (6 enteric coated tablets of Asacol 400 mg) in healthy volunteers under fasting conditions was about 135 L/h (geometric mean, CV% = 61.43%, intersubject). The median elimination half- life was 20 h ranging from 5 to 77 h. About 25% of the total dose administered was recovered in the urine within 60 h after fasted administration mainly as N-acetyl mesalazine and as the parent compound (about 1 %).

Linearity/non-linearity
In a cross-over design with 3 test periods and 3 ascending oral doses of Asacol 400 mg enteric coated Tablets administered 6 hourly over 4 consecutive doses (total daily dose of mesalazine: 3200, 4800, 6400 mg) it was shown that the absorption and elimination kinetics for mesalazine are dose independent for the 3 doses evaluated.
For each dose, about ¾ of the dose was available for the therapeutic activity for the colon. Only about ¼ of each dose was absorbed and excreted in the urine, primarily as the metabolite. Based on urine drug excretion, plasma drug Cmax’s and the combined plasma AUC’s, there was a linear dose response for the 3 Asacol tablet doses. The clinical performance of Asacol 400 should be similar for the range of doses evaluated in this study.

Pharmacokinetic/ pharmacodynamics relationship(s)
No specific studies have been performed.