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Giazo

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Giazo

CLINICAL PHARMACOLOGY

Mechanism Of Action

Balsalazide is a prodrug of mesalamine (5-aminosalicylic acid, 5-ASA). The mechanism of action of 5-ASA is unknown, but appears to be local to the colonic mucosa 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 ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites in the colon.

Pharmacokinetics

Following oral administration, balsalazide is cleaved by azoreductases produced by anaerobic bacteria found in the gut, to release equimolar quantities of 5-ASA, the active moiety, and 4-aminobenzoyl-s-alanine (4-ABA), a carrier moiety. Both of these moieties are N-acetylated to form N-Ac-5-ASA and N-Ac-4-ABA, respectively.

Absorption

After single-dose administration of 3.3 g GIAZO in 18 healthy subjects, the median time of peak plasma concentration (Tmax) was 0.5 hr for balsalazide, while the median Tmax was 12 hr for both 5-ASA and N-Ac-5-ASA (Table 2). Pharmacokinetic parameters exhibited high variability, with %CV ranging from 31% to 67% for AUC and from 27% to 68% for Cmax.

Pharmacokinetics were also estimated in healthy volunteers after repeated doses of 3.3 g GIAZO tablets every 12 hours for 7 days. After multiple doses, steady-state was achieved after about 3 days for balsalazide and all metabolites. The AUC and Cmax were the highest for N-Ac-5-ASA, followed by 5-ASA and balsalazide. There was minimal accumulation of balsalazide, as suggested by a 1.2-fold increase in AUC; however, a relatively larger increase in the systemic exposure to metabolites was observed at steady-state. The accumulation ratios based on AUC for the metabolites were 6.1 for 5-ASA, 3.6 for N-Ac-5-ASA, 4.8 for 4-ABA, and 3.6 for N-Ac-4-ABA.

Table 2: Pharmacokinetic Parameters for Balsalazide and Metabolites (5- ASA and N-Ac-5-ASA) Following Single- and Repeated-Doses (Q12) of 3.3 g Balsalazide Disodium as GIAZO (N=18)

Parameter Single Dose Repeated Dose
Mean SD Mean SD
Cmax (mcg/mL)
  Balsalazide 0.3 .2 0. 0.3 0.2
  5-ASA 0.5 0.3 1.5 0.6
  N-Ac-5-ASA 1.2 0.4 2.2 0.6
Tmaxa (hours)
  Balsalazide 0.5 (0.5-2) 0.5 (0.5-2)
  5-ASA 12 (8-16) 12 (1.5-16)
  N-Ac-5-ASA 12 (8-16) 10 (1-16)
AUCtau (mcg•h/mL)
  Balsalazide 1.3 0.7 1.6 0.9
  5-ASA .2 2. 1.6 13.4 6.3
  N-Ac-5-ASA 5.9 .9 2. 21 6.4
AUC0-∞ (mcg•h/mL)
  Balsalazide 1.4 0.8 NA NA
  5-ASA 8.5 3.9 NA NA
  N-Ac-5-ASA 33.5 14.1 NA NA
b (hour)
  Balsalazide 1.9 0.7 8.4 12.4
  5-ASA 9.5b 10.1 9.0 8.6
  N-Ac-5-ASA 10.4b 17.6 7.2 6.8
a Expressed as median and range.
b N=17

Food effect

After administration of single dose of 3.3 g (3 1.1 g tablets) of GIAZO with a high-fat meal in healthy volunteers, the AUC of balsalazide was unaffected compared to fasted administration, but the presence of food reduced both peak concentrations and AUC of the metabolites 5-ASA and N-Ac-5-ASA. A high fat meal increased the median Tmax for balsalazide from 0.5 to 2 hours; for 5-ASA from 12 to 24 hours; and for N-Ac-5-ASA from 12 to 24 hours. Under fed conditions, the mean Cmax was reduced by 44% for balsalazide, 65% for 5-ASA, and 48% for N-Ac-5-ASA. No significant changes were observed for AUC0-∞ for balsalazide; however, AUC0-∞ was reduced for 5-ASA by 46% and for N-Ac-5-ASA by 17%.

Distribution

The binding of balsalazide to human plasma proteins was ≥ 99%; 5-ASA and N-Ac-5- ASA were 43% and 78% bound, respectively, to plasma proteins.

Metabolism and Excretion

Following oral administration, balsalazide is cleaved by bacterial azoreduction to release equimolar quantities of 5-ASA, the active moiety, and 4-ABA, a carrier moiety. Mesalamine (5-ASA) and 4-ABA are further acetylated to N-Ac-5-ASA and N-Ac-4- ABA, respectively in the intestinal mucosa and liver. The terminal half-life was 1.9 h for balsalazide, 9.5 h for 5-ASA, and 10.5 h for N-Ac-5-ASA.

At steady-state following administration of repeated doses of 3.3 g GIAZO every 12 hours in healthy volunteers, the combined % of dose excreted in urine for balsalazide and its metabolites over 12 hours was 23%. The mean % of dose excreted in urine over 12 hours was 0.16% for balsalazide, 4.6% for 5-ASA, 15.6% for N-Ac-5- ASA, 0.40% for 4-ABA, and 1.8% for N-Ac-4-ABA.

Clinical Trials

Ulcerative Colitis

A double-blind, placebo-controlled, multi-center trial was conducted in 250 adult patients with mildly to moderately active ulcerative colitis. The trial population was primarily white (84%), had a mean age of 44 years (7% age 65 years or older), and 49% were men. Disease activity was assessed using a modified Mayo Disease Activity Index1 (MMDAI), which was a sum of four subscores (bowel frequency, rectal bleeding, endoscopic appearance, and physician's global assessment), each ranging from 0 to 3, with higher scores indicating worse disease. The median baseline MMDAI score was 8 and the median baseline rectal bleeding subscore was 2. Patients were randomized 2:1 to receive 8 weeks of treatment with either GIAZO 3.3 g twice daily or placebo.

The primary efficacy endpoint was the proportion of patients that achieved clinical improvement and improvement in the rectal bleeding subscale of the MMDAI at the end of 8 weeks of treatment. Clinical Improvement was defined as having both a ≥ 3 point improvement from baseline in the MMDAI score and a ≥ 1 point improvement from baseline in the rectal bleeding subscore. Two key secondary efficacy endpoints were the proportion of patients with Clinical Remission and Mucosal Healing at the end of 8 weeks of treatment. Clinical Remission was defined as a score of 0 for rectal bleeding and a combined score of ≤ 2 for bowel frequency and physician's assessment using the MMDAI subscale; the endoscopic sub-score was not considered in this definition. Mucosal Healing was defined as an endoscopy/sigmoidoscopy score of 0 or 1, where a score of 1 could include signs of erythema or decreased vascular pattern; by definition, the presence of friability indicated a score of 2 or 3.

After 8 weeks of treatment, the proportion of patients who met the definition of Clinical Improvement was greater for the GIAZO-treated group compared to the placebo group (Table 3).

Table 3: Proportion of Patients with Clinical Improvement* at Week 8 for the Total Population and by Gender Subgroups

  GIAZO Placebo p-value
Total Population 55% 40% 0.0237
Males 57% 20%
Females 54% 58%
* Clinical Improvement: ≥ 3 improvement in MMDAI score and ≥ 1 point improvement in rectal bleeding.

These differences were statistically significant in the overall population; however, these effects were entirely driven by the results in the male subpopulation. With adjustment for multiplicity, statistically significant differences were also seen in the male patients for Clinical Remission (35% with GIAZO vs. 13% for placebo) and for Mucosal Healing (52% with GIAZO vs. 20% for placebo). Effectiveness of GIAZO was not demonstrated in the female subpopulation in the clinical trial.

REFERENCES

1. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mild to moderately active ulcerative colitis: a randomized study. N Engl J Med. 1987;317:1625-9.

Last reviewed on RxList: 2/13/2014
This monograph has been modified to include the generic and brand name in many instances.

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