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Asacol HD

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Asacol HD

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

Pharmacokinetics

Plasma concentrations of mesalamine (5-aminosalicylic acid; 5-ASA) and its metabolite, N-acetyl-5aminosalicylic acid (N-Ac-5-ASA) are highly variable following administration of Asacol HD tablets. The time to peak plasma concentration (tmax) is prolonged for mesalamine and N-Ac-5-ASA with the median values from various studies ranging from 10 to 16 hours, reflecting the delayed-release characteristics. Based on cumulative urinary recovery of mesalamine and N-Ac-5-ASA from single dose studies in healthy volunteers, approximately 20% of the orally administered mesalamine in Asacol HD tablets is systemically absorbed. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA which is excreted mainly by the kidney. The PK parameters following administration of 1600 mg three times daily in healthy subjects are shown in Table 2.

Table 2 : Mean (± S.D.) PK parameters in healthy subjects following administration of two 800 mg tablets three times daily for 6 days (n=16)

  Mesalamine N-Ac-5-ASA
AUCtau (mcg h/mL) 20 ± 14 25 ± 11
Cmax (mcg/mL) 5.0 ± 4.0 4.6 ± 2.5
t½ (h) 12.6 ± 10.9* 23.6 ± 11.2#
* n=11, #n=6

A high fat meal does not affect the extent of systemic exposure to mesalamine after single-dose administration of Asacol HD, but mesalamine Cmax decreases by 47% and tmax is delayed by 14 hours under fed conditions.

One Asacol HD (mesalamine delayed-release tablets, oral) 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets. In a single dose, cross-over pharmacokinetic study in 20 healthy volunteers, the mean mesalamine Cmax was 36% lower and the mean mesalamine AUC was 25% lower with administration of one Asacol HD (mesalamine delayed-release tablets, oral) 800 mg tablet relative to two Asacol 400 mg tablets. Because the mechanism of action of mesalamine appears to be topical, the impact of these differences in measures of systemic exposure on clinical efficacy is not known.

Animal Toxicology and/or Pharmacology

In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 4.8 g/day dose for a 50 kg person.)

Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (1.3 to 1.7 times the recommended human dose). Doses of 170 and 360 mg/kg/day (about 0.3 and 0.6 times the recommended human dose) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia.

In mice, oral doses of 4000 mg/kg/day (approximately 3.4 times the recommended human dose) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.

In dogs, single doses of 6000 mg (approximately 6.25 times the recommended human dose) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (0.5 times the recommended human dose).

Clinical Studies

Moderately Active Ulcerative Colitis

The efficacy of Asacol HD (mesalamine delayed-release tablets, oral) at 4.8 g/day was studied in a six-week, randomized, double-blind, active-controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as a Physician's Global Assessment (PGA) score of 2; the PGA is a four-point scale (0-3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings.

Patients were randomized 1:1 to the Asacol HD 4.8 g/day group (two Asacol HD tablets three times a day) or the Asacol (mesalamine) 2.4 g/day group (two Asacol 400 mg tablets three times a day). (One Asacol HD (mesalamine delayed-release tablets, oral) 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets).

Patients characteristically had a history of previous use of oral 5-ASAs (86%), steroids (41%), and rectal therapies (49%), and demonstrated clinical symptoms of three or more stools over normal per day (87%) and obvious blood in the stool most or all of the time (70%). The study population was primarily Caucasian (97%), had a mean age of 43 years (8% aged 65 years or older), and included slightly more males (56%) than females (44%).

The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA. Treatment success rates were similar in the two groups: 70% in the Asacol HD (mesalamine delayed-release tablets, oral) group and 66% in the Asacol group (difference: 5%; 95% CI: [-1.9%, 11.2%]).

A second controlled study supported the efficacy of Asacol HD at 4.8 g/day. Treatment success was 72% in patients with moderately active UC treated with Asacol HD (mesalamine delayed-release tablets, oral) .

Last reviewed on RxList: 10/23/2009
This monograph has been modified to include the generic and brand name in many instances.

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