Colazal Pharmacology, Pharmacokinetics, Studies, Metabolism - Balsalazide

Colazal Pharmacology, Pharmacokinetics, Studies, Metabolism - Balsalazide

CLINICAL PHARMACOLOGY

Balsalazide disodium is delivered intact to the colon where it is cleaved by bacterial azoreduction to release equimolar quantities of mesalamine, which is the therapeutically active portion of the molecule, and 4-aminobenzoyl-(beta)-alanine. The recommended dose of 6.75 grams/day, for the treatment of active disease, provides 2.4 grams of free 5-aminosalicylic acid to the colon.

The 4-aminobenzoyl-(beta)-alanine carrier moiety released when balsalazide disodium is cleaved is only minimally absorbed and largely inert. The mechanism of action of 5-aminosalicylic acid is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that 5-aminosalicylic acid diminishes inflammation by blocking production of arachidonic acid metabolites in the colon.

Pharmacokinetics:    COLAZAL ™ capsules contain granules of balsalazide disodium which are insoluble in acid and designed to be delivered to the colon intact. Upon reaching the colon, bacterial azoreductases cleave the compound to release 5-aminosalicylic acid the therapeutically active portion of the molecule, and 4-aminobenzoyl-(beta)-alanine.

Absorption:   In healthy individuals, the systemic absorption of intact balsalazide was very low and variable. The mean C _max occurs approximately 1-2 hours after single oral doses of 1.5 grams or 2.25 grams. The absolute bioavailability of this compound was not determined. In a study of ulcerative colitis patients receiving balsalazide, 1.5 grams twice daily, for over one year, systemic drug exposure, based on mean AUC values, was up to 60 times greater (8 ng*hr/mL to 480 ng*hr/mL) after equivalent multiple doses of 1.5 grams twice daily when compared to healthy subjects who received the same dose. There was a large intersubject variability in the plasma concentration of balsalazide versus time profiles in all studies, thus its half-life could not be determined. The effect of food intake on the absorption of this compound was not studied.

Distribution:   The binding of balsalazide to human plasma proteins was ≥ 99%.

Metabolism:   The products of the azoreduction of this compound, 5-aminosalicylic acid and 4-aminobenzoyl-(beta)-alanine, and their N-acetylated metabolites have been identified in plasma, urine and feces.

Elimination:   Less than 1% of an oral dose was recovered as parent compound, 5-aminosalicylic acid or 4-aminobenzoyl-(beta)-alanine in the urine of healthy subjects after single and multiple doses of COLAZAL ™, while up to 25% of the dose was recovered as the N-acetylated metabolites. In a study with 10 healthy volunteers, 65% of a single 2.25 grams dose of COLAZAL ™ was recovered as 5-aminosalicylic acid, 4-aminobenzoyl-(beta)-alanine, and the N-acetylated metabolites in feces, while <1% of the dose was recovered as parent compound.

In a study that examined the disposition of balsalazide in patients who were taking 3-6 grams of COLAZAL ™ daily for more than one year and who were in remission from ulcerative colitis, less than 1% of an oral dose was recovered as intact balsalazide in the urine. Less than 4% of the dose was recovered as 5-aminosalicylic acid, while virtually no 4-aminobenzoyl-(beta)-alanine was detected in urine. The urinary recovery of the N-acetylated metabolites comprised 20-25% of the balsalazide dose. No fecal recovery studies were performed in this population.

Special Populations

Geriatric:   No information is available for the geriatric population.

Pediatric:   The safety and effectiveness of balsalazide in the pediatric population have not been established.

Gender:   No adequate and well-controlled studies which examine balsalazide in males versus females are available.

Renal Insufficiency:   No adequate and well-controlled studies which examine balsalazide disposition in patients with mild, moderate, and severe renal impairment are available.  

Hepatic Insufficiency:   No information is available for patients with hepatic impairment.

Race:   No information is available which examines balsalazide in different races.

Pharmacodynamic/Pharmacokinetic Relationship:   No information is available.

Drug-Drug Interactions:   Neither in vitro nor in vivo drug-drug interaction studies have been performed with balsalazide.

CLINICAL TRIALS

Two randomized, double blind studies were conducted.

In the first trial, 103 patients with active mild to moderate ulcerative colitis with sigmoidoscopy findings of friable or spontaneously bleeding mucosa were randomized and treated with balsalazide 6.75 grams/day or balsalazide 2.25 grams/day. The primary efficacy endpoint was reduction of rectal bleeding and improvement of at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment (PGA)). Outcome assessment for rectal bleeding at each interim period (week 2, 4, and 8) encompassed a 4 day period (96 hours). Results demonstrated a statistically significant difference between high and low doses of COLAZAL ™.

A second study, conducted in Europe, confirmed findings of symptomatic improvement.