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Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: It has been established that mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn's disease (Prolonged-release tablet and Suppository).
Based on clinical results, the therapeutic value of mesalazine after oral and rectal administration appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mesalazine.
Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4, and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease (IBD). The mechanism of action of mesalazine is not fully understood although mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa has been implicated. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leucotriene production, and scavenge for free radicals. It is currently unknown which, if any, of these mechanisms play a predominant role in the clinical efficacy of mesalazine.
Prolonged-release tablet and Prolonged-release granules: The risk of colorectal cancer (CRC) is slightly increased in ulcerative colitis. Observed effects of mesalazine in experimental models and patient biopsies support the role of mesalazine in prevention of colitis-associated CRC, with down regulation of both inflammation dependent and non-inflammation dependent signalling pathways involved in the development of colitis-associated CRC.
However data from meta-analyses, including both referral and non-referral populations, provide inconsistent clinical information regarding the benefit of mesalazine in the carcinogenesis risk associated with ulcerative colitis.
Pharmacokinetics: General characteristics of the active substance: Disposition and local availability: The therapeutic activity of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa.
Prolonged-release tablet and Prolonged-release granules: PENTASA prolonged release tablets/granules consist of ethylcellulose-coated microgranules of mesalazine (the tablet disintegrate upon administration to coated microgranules) and enter the duodenum within an hour of administration, independent of food co-administration. Mesalazine is continuously released from the coated microgranules throughout the gastrointestinal tract in any enteral pH conditions.
Suppository and Rectal suspension: PENTASA suppositories and rectal suspensions are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. Suppositories cover the rectum. Rectal suspensions have been shown to reach and cover the descending colon.
Absorption: Prolonged-release tablet and Prolonged-release granules: Bioavailability of PENTASA after oral administration can be estimated to approx. 30%, based on urine recovery data in healthy volunteers. Maximum plasma concentrations are seen 1-6 hours post-dose. A once-daily dosing regimen of mesalazine (1 × 4 g/d) and a twice-daily dosage (2 × 2 g/d) results in a comparable systemic exposure (AUC) over 24 hours and indicate a continuous release of mesalazine from the formulation over the treatment period. Steady-state is reached after a treatment period of 5 days following oral administration. (See Table 1.)
Click on icon to see table/diagram/imageThe transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic exposure may be increased.
Suppository and Rectal suspension: The absorption following rectal administration is low, and depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2 g (1 g x 2), approximately 10% of the dose (suppository) and about 15-20% (rectal suspension) are absorbed after administration.
Distribution: Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.
Metabolism: Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine) principally by NAT-1. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient.
Prolonged-release tablet and Prolonged-release granules: The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500 mg × 3 and 2 g × 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Elimination: Due to the continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, once the formulation is not present in the GI tract elimination will follow the plasma half-life of orally or iv administered uncoated mesalazine, which is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
Characteristics in Patients: Prolonged-release tablet and Prolonged-release granules: Pathophysiologic changes such as diarrhoea and increased bowel acidity observed during active inflammatory bowel disease has only a minor impact on the delivery of mesalazine to the intestinal mucosa after oral administration. A urine excretion 20-25% of the daily dose has been observed in subjects with accelerated intestinal transit. Likewise, a corresponding increase in faecal excretion has been seen.
Rectal suspension: The systemic exposure following administration of PENTASA rectal suspension has been shown to be significantly decreased in patients with active ulcerative colitis as compared to those in remission.
Toxicology: Preclinical Safety Data: Toxic renal effects have been demonstrated in all species tested. Rat and monkey dosages and plasma concentrations at the No Observed Adverse Effect Levels (NOAELs) exceed those used in humans by a factor of 2-7.2.
No significant toxicity associated with the gastrointestinal tract, liver or haematopoietic system in animals has been observed.
In vitro test systems and in-vivo studies showed no evidence of mutagenic or clastogenic effects. Studies of the tumourigenic potential carried out in mice and rats showed no evidence of any substance-related increase in the incidence of tumours.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryo-foetal development, parturition or postnatal development.
Mesalazine is deemed not to pose a risk to the environment at the doses prescribed for use in patients.
