Mechanism Of Action
The mechanism of action of mesalamine (5-ASA) is unknown,
but appears to be local to the intestinal 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.
The pharmacokinetics of 5-ASA and its metabolite,
N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a single and
multiple oral doses of 1.5 g APRISO in a crossover study in healthy subjects
under fasting conditions. In the multiple-dose period, each subject received
APRISO 1.5 g (4 x 0.375 g capsules) every 24 hours (QD) for 7 consecutive days.
Steady state was reached on Day 6 of QD dosing based on trough concentrations.
After single and multiple doses of APRISO, peak plasma
concentrations were observed at about 4 hours post dose. At steady state,
moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC0-24) to
5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of APRISO.
Pharmacokinetic parameters after a single dose of 1.5 g
APRISO and at steady state in healthy subjects under fasting condition are
shown in Table 2.
Table 2: Single Dose and Multiple Dose Mean (±SD)
Plasma Pharmacokinetic Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA after
1.5 g APRISO Administration in Healthy Subjects
||11 ± 5
||17 ± 6
||14 ± 5
||2.1 ± 1.1
||2.7 ± 1.1
||4 (2, 16)
||4 (2, 8)
||9 ± 7
||10 ± 8
||26 ± 6
||37 ± 9
||51 ± 23
||2.8 ± 0.8
||3.4 ± 0.9
||4 (4, 12)
||5 (2, 8)
||12 ± 11
||14 ± 10
bHarmonic mean (pseudo SD);
cafter 7 days of treatment
In a separate study (n = 30), it was observed that under
fasting conditions about 32% ± 11% (mean ± SD) of the administered dose was
systemically absorbed based on the combined cumulative urinary excretion of
5-ASA and N-Ac-5-ASA over 96 hours post-dose.
The effect of a high fat meal intake on absorption of
mesalamine granules (the same granules contained in APRISO capsules) was
evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules
in sachet (2 x 0.8 g) following an overnight fast or a high fat meal in a
crossover study. Under fed conditions, tmax for both 5-ASA and N-Ac-5-ASA was
prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmax
for 5-ASA, but a 27% increase in the cumulative urinary excretion of 5-ASA was
observed with a high fat meal. The overall extent of absorption of N-Ac-5-ASA
was not affected by a high fat meal. As APRISO and mesalamine granules in
sachet were bioequivalent, APRISO can be taken without regard to food.
In an in vitro study, at 2.5 μg/mL, mesalamine and
N-Ac-5-ASA are 43 ± 6% and 78 ± 1% bound, respectively, to plasma proteins.
Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at
concentrations ranging from 1 to 10 μg/mL.
The major metabolite of mesalamine is
N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase
activity in the liver and intestinal mucosa.
Following single and multiple doses of APRISO, the mean
half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of
the approximately 32% of the dose absorbed, about 2% of the dose was excreted
unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA.
In Vitro Drug-Drug Interaction Study
In an in vitro study using human liver microsomes, 5-ASA
and its metabolite, N-Ac-5-ASA, were shown not to inhibit the major CYP enzymes
evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). Therefore, mesalamine
and its metabolite are not expected to inhibit the metabolism of other drugs
that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
Animal Toxicology And/Or Pharmacology
Animal studies with mesalamine (13-week and 26-week oral
toxicity studies in rats, and 26-week and 52- week oral toxicity studies in
dogs) have shown the kidney to be the major target organ of mesalamine toxicity.
Oral doses of 40 mg/kg/day (about 0.20 times the human dose, on the basis of
body surface area) produced minimal to slight tubular injury, and doses of 160
mg/kg/day (about 0.90 times the human dose, on the basis of body surface area)
or higher in rats produced renal lesions including tubular degeneration,
tubular mineralization, and papillary necrosis. Oral doses of 60 mg/kg/day
(about 1.1 times the human dose, on the basis of body surface area) or higher
in dogs also produced renal lesions including tubular atrophy, interstitial
cell infiltration, chronic nephritis, and papillary necrosis.
Single oral doses of 800 mg/kg (about 2.2 times the
recommended human dose, on the basis of body surface area) and 1800 mg/kg
(about 9.7 times the recommended human dose, on the basis of body surface area)
of mesalamine were lethal to mice and rats, respectively, and resulted in
gastrointestinal and renal toxicity.
Two similar, randomized, double-blind,
placebo-controlled, multi-center studies were conducted in a total of 562 adult
patients in remission from ulcerative colitis. The study populations had a mean
age of 46 years (11% age 65 years or older), were 53% female, and were
primarily white (92%).
Ulcerative colitis disease activity was assessed using a
modified Sutherland Disease Activity Index1 (DAI), which is a sum of
four subscores based on stool frequency, rectal bleeding, mucosal appearance on
endoscopy, and physician's rating of disease activity. Each subscore can range
from 0 to 3, for a total possible DAI score of 12.
At baseline, approximately 80% of patients had a total
DAI score of 0 or 1.0. Patients were randomized 2:1 to receive either APRISO
1.5 g or placebo once daily in the morning for six months. Patients were assessed
at baseline, 1 month, 3 months, and 6 months in the clinic, with endoscopy
performed at baseline, at end of study, or if clinical symptoms developed.
Relapse was defined as a rectal bleeding subscale score of 1 or more and a
mucosal appearance subscale score of 2 or more using the DAI. The analysis of
the intent-to-treat population was a comparison of the proportions of patients
who remained relapse-free at the end of six months of treatment. For the table
below (Table 3) all patients who prematurely withdrew from the study for any
reason were counted as relapses.
In both studies, the proportion of patients who remained
relapse-free at six months was greater for APRISO than for placebo.
Table 3: Percentage of Patients Relapse-Free* through
6 Months in APRISO Maintenance Studies
||APRISO 1.5 g/day % (# no relapse/N)
||Placebo % (# no relapse/N)
||Difference (95% C.I.)
||17% (5.5, 29.2)
||12% (0, 24.5)
|*Relapse counted as rectal bleeding score ≥ 1 and
mucosal appearance score ≥ 2, or premature withdrawal from study.
Examination of gender subgroups did not identify
difference in response to APRISO among these subgroups. There were too few
elderly and too few African-American patients to adequately assess difference
in effects in those populations.
The use of APRISO for treating ulcerative colitis beyond
six months has not been evaluated in controlled clinical trials.
1. Sutherland LR, Martin F, Greer S, Robinson M,
Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of
distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology