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Sulfasalazine is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine component is therapeutically active in ulcerative colitis. The usual oral dose of sulfasalazine for active ulcerative colitis in adults is 2 to 4 g per day in divided doses. Four grams of sulfasalazine provide 1.6 g of free mesalamine to the colon.
The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, ie, prostanoids, and through the lipoxygenase pathways, ie, 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.
Human Pharmacokinetics and Metabolism
PENTASA is an ethylcellulose-coated, controlled-release formulation of mesalamine designed to release therapeutic quantities of mesalamine throughout the gastrointestinal tract. Based on urinary excretion data, 20% to 30% of the mesalamine in PENTASA is absorbed. In contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalamine is approximately 80% absorbed.
Plasma mesalamine concentration peaked at approximately 1 μg/mL 3 hours following a 1-g PENTASA dose and declined in a biphasic manner. The literature describes a mean terminal half-life of 42 minutes for mesalamine following intravenous administration. Because of the continuous release and absorption of mesalamine from PENTASA throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration. N-acetylmesalamine, the major metabolite of mesalamine, peaked at approximately 3 hours at 1.8 μg/mL, and its concentration followed a biphasic decline. Pharmacological activities of N-acetylmesalamine are unknown, and other metabolites have not been identified.
Oral mesalamine pharmacokinetics were nonlinear when PENTASA capsules were dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma concentrations increasing about nine times, from 0.14 μg/mL to 1.21 μg/mL, suggesting saturable first-pass metabolism. N-acetylmesalamine pharmacokinetics were linear.
About 130 mg free mesalamine was recovered in the feces following a single 1-g PENTASA dose, which was comparable to the 140 mg of mesalamine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g. Elimination of free mesalamine and salicylates in feces increased proportionately with PENTASA dose. N-acetylmesalamine was the primary compound excreted in the urine (19% to 30%) following PENTASA dosing.
In two randomized, double-blind, placebo-controlled, dose-response trials (UC-1 and UC-2) of 625 patients with active mild to moderate ulcerative colitis, PENTASA, at an oral dose of 4 g/day given 1 g four times daily, produced consistent improvement in prospectively identified primary efficacy parameters, PGA, Tx F, and SI as shown in the table below.
The 4-g dose of PENTASA also gave consistent improvement in secondary efficacy parameters, namely the frequency of trips to the toilet, stool consistency, rectal bleeding, abdominal/rectal pain, and urgency. The 4-g dose of PENTASA induced remission as assessed by endoscopic and symptomatic endpoints.
In some patients, the 2-g dose of PENTASA was observed to improve efficacy parameters measured. However, the 2-g dose gave inconsistent results in primary efficacy parameters across the two adequate and well-controlled trials.
|Parameter Evaluated||Clinical Trial UC-1||Clinical Trial-UC-2|
|* p < 0.05 vs placebo.
PGA: Physician Global Assessment: proportion of patients with complete or marked improvement.
Tx F: Treatment Failure: proportion of patients developing severe or fulminant UC requiring steroid therapy or hospitalization or worsening of the disease at 7 days of therapy, or lack of significant improvement by 14 days of therapy.
SI: Sigmoidoscopic Index: an objective measure of disease activity rated by a standard (15-point) scale that includes mucosal vascular pattern, erythema, friability, granularity/ulcerations, and mucopus: improvement over baseline.
† Defined as complete resolution of symptoms plus improvement of endoscopic endpoints. To be considered in remission, patients had a “1” score for one of the endoscopic components (mucosal vascular pattern, erythema, granularity, or friability) and “0” for the others.
Last reviewed on RxList: 8/9/2013
This monograph has been modified to include the generic and brand name in many instances.
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