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
Elmiron Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentosan
Elmiron Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentosan
CLINICAL PHARMACOLOGY
General
Pentosan polysulfate sodium
is a low molecular weight
heparin-like compound. It has anticoagulant
and fibrinolytic effects. The mechanism of action
of pentosan polysulfate sodium
in interstitial
cystitis is not known.
Pharmacokinetics
Absorption: In preliminary
clinical studies with
different doses of radio labeled pentosan polysulfate sodium,
absorption was approximately
3% of the administered dose
(n=3).
Distribution: Preclinical studies with parenterally administered
radio labeled pentosan polysulfate sodium
showed distribution
to the uroepithelium of the genitourinary
tract with lesser amounts
found in the liver, spleen,
lung, skin, periosteum,
and bone marrow. Erythrocyte
penetration is low
in animals.
Metabolism: Preliminary literature studies of metabolism
in 5 healthy volunteers with radio labeled drug
suggest that 68% of the dose, at about 1 hour after IV
administration, undergoes partial desulfation in the liver and spleen.
In another study of 3 healthy
volunteers, partial depolymerization occurs in the kidney. Both
the desulfation and depolymerization
can be saturated with continued dosing.
Excretion: In preliminary
clinical studies in
8 healthy male
volunteers, the elimination
half-life of pentosan
polysulfate sodium had
a mean value at 24 hours
after IV injection
of 40 mg. The elmination half-life
in urine following orally administered radio labeled pentosan polysulfate
sodium was determined to be 4.8 hours for the unchanged drug.
In preliminary human
studies in 3 healthy
male volunteers, after
single doses of radio labeled drug,
urinary excretion
averaged 3.5% of the administered dose. After multiple
doses of pentosan polysulfate sodium,
urine excretion of radioactivity
averaged 11% of the administered dose.
Further analyses of the urinary
fraction obtained after
repeated dosing showed that about 3% of the dose
may be unchanged pentosan polysulfate sodium.
Special Populations: Dose adjustments in geriatric patients
and in patients with hepatic
or renal impairment
were not studied.
Pharmacodynamics
The mechanism by
which pentosan polysulfate sodium achieves its effects in patients
is unknown. In preliminary
clinical models, pentosan
polysulfate sodium adhered
to the bladder wall
mucosal membrane. The drug
may act as a buffer
to control cell
permeability preventing
irritating solutes in the urine
from reaching the cells.
Food effects: The effect
of food on absorption
of pentosan polysulfate sodium is not known. In
clinical trials, Elmiron®
was administered with water
1 hour before or 2 hours after meals.
Drug-Drug Interactions
Not studied.
CLINICAL TRIALS
Elmiron® was evaluated in two clinical
trials for the relief of pain
in patients with chronic
interstitial cystitis
(IC). All patients met the NIH
definition of IC
based upon the results of cystoscopy, cytology, and biopsy. One
blinded, randomized, placebo
controlled study evaluated 151 patients (145 women, 5 men, 1 unknown)
with a mean age
of 44 years (range 18 to 81). Approximately equal numbers of patients
received either placebo
or Elmiron® 100 mg
three times a day for 3 months. Clinical improvement in bladder
pain was based upon the
patient’s own assessment. In
this study, 28/74 (38%) of patients who received Elmiron® and
13/74 (18%) of patients who received placebo,
showed greater than 50% improvement in bladder
pain (p=0.005).
A second clinical
trial, the physician’s usage study, was a prospectively designed
retrospective analysis
of 2499 patients who received Elmiron® 300 mg
a day without blinding. Of the 2499 patients, 2220 were women, 254
were men, and 25 were of unknown sex. The patients had a mean
age of 47 years and 23%
were over 60 years of age. By 3 months, 1307 (52%) of the patients
had dropped out or were ineligible for analysis, overall, 1192 (48%)
received Elmiron® for 3 months; 892 (36%) received
Elmiron® for 6 months; and 598 (24%) received Elmiron®
for one year.
Patients had unblinded evaluations every 3 months for the patient’s
rating of overall change in pain
in comparison to baseline
and for the difference calculated in “pain/discomfort” scores. At
baseline, pain/discomfort
scores for the original 2499 patients were severe or unbearable
in 60%, moderate in 33% and mild or none in 7% of patients. The
extent of the patients’ pain improvement is shown in Table 1.
Table 1:
Pain Scores in Reference to Baseline in Open Label Physician’s
Usage Study (N=2499)1 |
| Efficacy Parameter |
3 months2 |
6 months2 |
| Patient Rating of Overall Change in Pain (Recollection
of difference between current
pain andbaseline
pain)3
Change in Pain/ Discomfort Score (Calculated difference
in scores at the time
point and baseline)4.
|
N=1161
Median=3
Mean=3.44
CI: (3.37, 3.51)
N=1440
Median=1
Mean=0.51
CI: (0.45, 0.57)
|
N=724
Median=4
Mean=3.91
CI: (3.83, 3.99)
N=904
Median=1
Mean=0.66
CI: (0.61, 0.71)
|
1 Trial not designed to detect onsetof pain
relief.
2 CI = 95% confidence interval
3 6-point scale: 1 = worse, 2 = no
better, 3 = slightly improved, 4 = moderately improved, 5 = greatly
improved, 6 = symptom
gone.
4 3-point scale: 1 = none or mild, 2 = moderate, 3 =
severe or unbearable.
At 3 months, 722/2499 (29%) of the patients originally in the study
had pain scores that improved
by one or two categories. By 6 months, in the 892 patients who continued
taking ELMIRON®, an additional 116/2499 (5%) of patients
had improved pain scores.
After 6 months, the percent of patients who reported the first onset
of pain relief
was less than 1.5% of patients who originally entered in the study
(see Table 2).
Table 2:
Number (%) of Patients with New Relief of Pain/Discomfort1
in the Open-Label Physician’s Usage Study (N=2499) |
| |
at 3 months2(n=1192)
|
at 6 months3(n=892) |
| Considering only the patients who continued
treatment |
722/1192 (61%) |
116/892 (13%) |
| Considering all the patients originally enrolled
in the study |
722/2499 (29%) |
116/2499 (5%) |
1First-time improvement in pain/discomfort score
by 1 or 2 categories.
2Number (%) of patients with improvement of pain/discomfort
score at 3 months when compared to baseline.
3Number (%) of patients without pain/discomfort improvement
at 3 months who had improvement at 6 months.
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