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Pharmacology: Pharmacodynamics: Mechanism of action: Mesalazine is an aminosalicylate. The mechanism of action of mesalazine is not fully understood, but appears to have a topical anti-inflammatory effect on the colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase and lipoxygenase pathways, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Mesalazine has the potential to inhibit the activation of nuclear factor kappa B (NFκB) and consequently the production of key proinflammatory cytokines. More recently, it has been proposed that impairment of PPAR-γ nuclear receptors (γ-form of the peroxisome proliferator-activated receptors) may be implicated in ulcerative colitis. PPAR-γ receptor agonists have shown efficacy in ulcerative colitis and evidence has been accumulating that the mechanism of action of mesalazine may be mediated by PPAR-γ receptors.
Pharmacodynamic effects: The Mezavant tablet contains a core of mesalazine (5-aminosalicylic acid) 1.2 g formulated in a multi-matrix system. This system is coated with methacrylic acid - methyl methacrylate copolymer (1:1) and methacrylic acid - methyl methacrylate copolymer (1:2), which are designed to delay release of mesalazine until exposure to approximately pH 7.
Clinical efficacy and safety: Mezavant was investigated in two similarly designed, Phase 3, placebo-controlled studies (SPD476-301 and SPD476-302) in 623 randomised patients with mild to moderate, active ulcerative colitis. Mezavant 2.4 g/day and 4.8 g/day administered with food achieved statistical superiority over placebo in terms of the number of patients achieving remission from ulcerative colitis after 8 weeks treatment. Using the Ulcerative Colitis Disease Activity Index (UC-DAI), remission was defined as a UC-DAI score of ≤1 with a score of 0 for rectal bleeding and stool frequency and at least a 1-point reduction in sigmoidoscopy score from baseline. Study SPD476-302 included a comparator, mesalazine pH 7-dependent modified-release 2.4 g/day (0.8 g administered in 3 divided doses), as an internal reference arm. On the primary variable of remission, the following results were achieved: See Table 1.
Click on icon to see table/diagram/imageA Phase 3, multicentre, randomized, double-blind, parallel group study was conducted in 107 paediatric patients aged 5 to 17 years (inclusive) with mild to moderate ulcerative colitis to evaluate the safety and efficacy of Mezavant in both double-blind acute (Double Blind Acute, DBA) and double-blind maintenance (Double Blind Maintenance, DBM) phases. Subjects received a low or a high weight-based dose of mesalazine in four weight groups: 18 kg to ≤23 kg (n=3), >23 kg to ≤35 kg (n=9), >35 kg to ≤50 kg (n=29), and >50 kg to ≤90 kg (n=66). The low dose ranged from 900 mg/day to 2,400 mg/day and the high dose ranged from 1,800 mg/day to 4,800 mg/day. Clinical effects of 1200 mg mesalazine tablets were evaluated in 66 subjects >50 kg to ≤90 kg in the age range 10 to 17 years.
Primary endpoint of the double-blind treatment phases was defined in terms of clinical response. Clinical response was defined as a partial Ulcerative Colitis Disease Activity Index (UC-DAI) score of ≤1 with a score of 0 for rectal bleeding and ≤1 for stool frequency and physician's global assessment = 0.
After 8 weeks of treatment in the DBA phase, 37.0% of subjects achieved a clinical response in the low-dose arm compared to 65.4% of subjects in the high-dose arm. The response rates at Week 8 in these dose arms were 50.0% and 56.3%, respectively, in subjects weighing >50 kg to ≤90 kg who received 1200 mg mesalazine tablets. In the DBM phase, after 26 weeks of treatment, 54.8% of subjects maintained a clinical response in the low-dose arm compared to 53.3% in the high-dose arm. The response rate at Week 26 was 50% in both dose arms in subjects weighing >50 kg to ≤90 kg who received 1200 mg mesalazine tablets. The study was not powered to assess differences between the low dose and high dose.
Pharmacokinetics: The mechanism of action of mesalazine (5-ASA) is not fully understood but appears to be topical, and therefore the clinical efficacy of mesalazine does not correlate with the pharmacokinetic profile. A major pathway of clearance of mesalazine is via metabolism to N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), which is pharmacologically inactive.
Absorption: Gamma-scintigraphy studies have shown that a single dose of mesalazine 1.2 g passed rapidly and intact through the upper gastrointestinal tract of fasted healthy volunteers. Scintigraphic images showed a trail of radio-labelled tracer through the colon, indicating that mesalazine had spread throughout this region of the gastrointestinal tract. Complete disintegration of mesalazine and complete release of mesalazine occurred after approximately 17.4 hours.
The total absorption of mesalazine from mesalazine 2.4 g or 4.8 g given once daily for 14 days to healthy volunteers was found to be approximately 21-22% of the administered dose.
In a single-dose study, mesalazine 1.2 g, 2.4 g and 4.8 g were administered in the fasted state to healthy subjects. Plasma concentrations of mesalazine were detectable after 2 hours (median) and reached a maximum by 9-12 hours (median) on average for the doses studied. The pharmacokinetic parameters are highly variable among subjects. Mesalazine systemic exposure in terms of area under the plasma concentration-time curve (AUC) was dose proportional between 1.2 g and 4.8 g mesalazine. Maximum plasma concentrations (Cmax) of mesalazine increased approximately dose proportionately between 1.2 g and 2.4 g and less than dose proportional between 2.4 g and 4.8 g mesalazine, with the dose normalised value at 4.8 g representing, on average, 74% of that at 2.4 g based on geometric means.
In a single- and multiple-dose pharmacokinetic study of mesalazine 2.4 and 4.8 g administered with standard meals in 56 healthy volunteers, plasma concentrations of mesalazine were detectable after 4 hours and were maximal by 8 hours after the single dose. At steady state (achieved generally by 2 days after dosing), 5-ASA accumulation was 1.1- to 1.4-fold for the 2.4 g and 4.8 g dose, respectively, above that expected on the basis of single-dose pharmacokinetics.
Administration of a single dose of mesalazine 4.8 g with a high fat meal resulted in further delay in absorption and mesalazine plasma levels were detectable after approximately 4 hours following dosing. However, a high fat meal increased systemic exposure of mesalazine (mean Cmax by 91%; mean AUC 16%) compared to results in the fasted state. Mesalazine was administered with food in the Phase 3 trials.
In a single-dose pharmacokinetic study of mesalazine, 4.8 g was administered in the fasted state to 71 healthy male and female volunteers [28 young (18-35 years); 28 elderly (65-75 years); 15 elderly (>75 years)]. Increased age resulted in increased systemic exposure (up to approximately 2-fold, based on AUC0-t, AUC0-∞ and Cmax) to mesalazine and its metabolite N-acetyl-5-aminosalicylic acid but did not affect the percentage of mesalazine absorbed. Increased age resulted in a slower apparent elimination of mesalazine, though there was high between-subject variability. Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
In a Phase 1, multicentre, open-label study (SPD476-112) in paediatric subjects (aged 5 to 17 years) diagnosed with UC, dosing of mesalazine was stratified by weight. Subjects were randomized to 1 of 3 possible treatments: 30, 60, or 100 mg/kg/day. Subjects received a total dose between 900 and 4,800 mg of mesalazine per day for 7 days. Pharmacokinetic steady-state was attained by Day 5 for all doses. On Day 7, systemic 5-ASA exposure, as measured by mean AUCss and Cmax,ss, increased in a dose proportional manner between 30 and 60 mg/kg/day of mesalazine. Between 60 and 100 mg/kg/day, systemic exposure of mesalazine increased in a sub-proportional manner. The mean percentage of mesalazine absorbed (based on urinary recovery) was similar at 30 and 60 mg/kg/day doses, being 29.4% and 27.0%, respectively. These results are similar to the percentage of mesalazine dose absorbed in adults from a previous study (SPD476-105), with values ranging from 17-22% for adult males and 24-32% for adult females.
The percentage of mesalazine absorbed was lower at 100 mg/kg/day 5-ASA (22.1%). There was no discernible difference of 5-ASA (and N-Ac-5-ASA) systemic exposure between children (aged 5 through 12 years) and adolescents (aged 13 through 17 years) with this weight-based (i.e., mg/kg) dosing paradigm.
Distribution: Following dosing of mesalazine, the distribution profile of mesalazine is presumed to be the same as that of other mesalazine-containing products. Mesalazine has a relatively small volume of distribution of approximately 18 L confirming minimal extravascular penetration of systemically available drug. Mesalazine is 43% bound and N-acetyl-5-aminosalicylic 78-83% bound to plasma proteins when in vitro plasma concentrations are up to 2.5 μg/mL and up to 10 μg/mL, respectively.
Biotransformation: The only major metabolite of mesalazine is N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive. Its formation is brought about by N-acetyltransferase-1 (NAT-1) activity in the liver and in the cytosol of intestinal mucosal cells.
Elimination: Elimination of absorbed mesalazine is mainly via the renal route following metabolism to N-acetyl-5-aminosalicylic acid (acetylation). However, there is also limited excretion of the parent drug in urine. Of the approximately 21-22% of the dose absorbed, less than 8% of the dose was excreted unchanged in the urine at steady state after 24 hours, compared with greater than 13% for N-acetyl-5-aminosalicylic acid. The apparent terminal half-lives for mesalazine and its major metabolite after administration of mesalazine 2.4 g and 4.8 g were, on average, 7-9 hours and 8-12 hours, respectively.
In adults, the mean renal clearances (CLR) were 1.8 L/h and 2.9 L/h for single doses of 2.4 g and 4.8 g, respectively, and slightly higher on Day 14 of multiple dosing: 5.5 L/h and 6.4 L/h for 2.4 g/day and 4.8 g/day. Mean renal clearances for the metabolite were higher, at approximately 12-15 L/h following single and multiple doses of mesalazine 2.4 g/day and 4.8 g/day.
In paediatric patients, the mean renal clearance of 5-ASA at steady state ranged from approximately 5.0-6.5 L/h (83-108 mL/min), which is similar to that observed with adult volunteers. There was a trend for CLR to decrease with increasing dose, and individual CLR estimates were highly variable. The mean CLR of N-Ac-5-ASA ranged from 10.0-16.2 L/h (166-270 mL/min), with a trend to decrease with increasing dose.
Hepatic impairment: There are no data in patients with hepatic impairment taking mesalazine. Systemic exposure to mesalazine increased by up to 2-fold in elderly subjects (>65 years, with a mean creatinine clearance of 68-76 mL/min) compared with younger adult subjects (18-35 years, mean creatinine clearance 124 mL/min) after a 4.8 g single dose of mesalazine.
Renal impairment: Systemic exposures in individual subjects were inversely correlated with renal function as assessed by estimated creatinine clearance.
Elderly: Pharmacokinetic data have not been investigated in elderly people.
The potential impact on the safe use of mesalazine in the elderly population in clinical practice should be considered. Furthermore, in patients with renal impairment, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions (see Precautions).
In different clinical studies with mesalazine, mesalazine plasma AUC in females appeared up to 2-fold higher than in males.
Based on limited pharmacokinetic data, 5-ASA and N-Ac-5-ASA pharmacokinetics appear comparable between Caucasian and Hispanic subjects.
Toxicology: Preclinical safety data: Effects in nonclinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
