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Apriso (Mesalamine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Each APRISO capsule is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine USP (5-aminosalicylic acid, 5-ASA), an anti-inflammatory drug.  The structural formula of mesalamine is:

Molecular Weight: 153.14
Molecular Formula: C7H7NO3

Each APRISO capsule contains granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.

The inactive ingredients of APRISO capsules are colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, simethicone emulsion, ethylacrylate/methylmethacrylate copolymer nonoxynol 100 dispersion, hypromellose, methacrylic acid copolymer, talc, titanium dioxide, triethyl citrate, aspartame, anhydrous citric acid, povidone, vanilla flavor, and edible black ink.

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

Absorption

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
Mesalamine (5-ASA)Single Dose
(n=24)
Multiple Dosec
(n=24)
a Median (range); b Harmonic mean (pseudo SD); c after 7days of treatment
  AUC0-24 (μg*h/mL) 11 ± 5 17 ± 6
  AUC0-inf (μg*h/mL) 14 ± 5 -
  Cmax (μg/mL) 2.1 ± 1.1 2.7 ± 1.1
  Tmax (h) a 4 (2, 16) 4 (2, 8)
  t½ (h)b 9 ± 7 10 ± 8
N-Ac-5-ASA    
  AUC0-24 (μg*h/mL) 26 ± 6 37 ± 9
  AUC0-inf (μg*h/mL) 51 ± 23 -
   Cmax (μg/mL) 2.8 ± 0.8 3.4 ± 0.9
  Tmax (h)a 4 (4, 12) 5 (2, 8)
  t½ (h)b 12 ± 11 14 ± 10
 

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.

Distribution

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.

Metabolism

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.

Elimination

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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 mg/kg/day.  These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1110 mg/m2), respectively, based on body surface area.  Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.  Mesalamine at oral doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area) was found to have no effect on fertility or reproductive performance in rats.

Animal Toxicology and/or Pharmacology

Renal Toxicity

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. 

Overdosage

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.

CLINICAL STUDIES

Ulcerative Colitis

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.)


  P-value  
*Relapse counted as rectal bleeding score ≥ 1 and mucosal appearance score ≥ 2, or premature withdrawal from study.
  Study 1     68% (143/209) 51% (49/96)  17% (5.5, 29.2)   <0.001
  Study 2     71% (117/164) 59% (55/93) 12% (0, 24.5) 0.046

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.

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