A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Pentasa Cr Pharmacology, Pharmacokinetics, Studies, Metabolism - Mesalamine CR
Pentasa Cr Pharmacology, Pharmacokinetics, Studies, Metabolism - Mesalamine CR
CLINICAL PHARMACOLOGY
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,
i.e., prostanoids, and through the lipoxygenase pathways, i.e., 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
Absorption
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.
Elimination
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.
CLINICAL TRIALS
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 1g four times daily,
produced consistent improvement in prospectively identified primary efficacy
parameters, PGA, TxF, 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 |
| PL |
PENTASA |
PL |
PENTASA |
| 4 g/day |
2 g/day |
4 g/day |
2 g/day |
| (n=90) |
(n=95) |
(n=97) |
(n=83) |
(n=85) |
(n=83) |
| PGA |
36% |
59%* |
57%* |
31% |
55%* |
41% |
| TxF |
22% |
9%* |
18% |
31% |
9%* |
17%* |
| SI |
-2.5 |
|
43 * |
-1.6 |
|
-2.6 |
| Remission |
12% |
26%* |
24%* |
12% |
27%* |
12% |
* p <0.05 vs placebo.
PGA: Physician Global Assessment: proportion of patients with complete
or marked improvement.
TxF: 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.
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