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
Relafen Pharmacology, Pharmacokinetics, Studies, Metabolism - Nabumetone
Relafen Pharmacology, Pharmacokinetics, Studies, Metabolism - Nabumetone
CLINICAL PHARMACOLOGY
Nabumetone is a nonsteroidal anti-inflammatory drug
(NSAID) that exhibits anti-inflammatory, analgesic
and antipyretic
properties in pharmacologic studies. As
with other nonsteroidal anti-inflammatory agents, its mode of action
is not known. However, the ability to inhibit prostaglandin
synthesis may be involved in the anti-inflammatory effect.
The parent compound
is a prodrug, which undergoes hepatic
biotransformation to the active component, 6-methoxy-2-naphthylacetic
acid (6MNA), that is a
potent inhibitor
of prostaglandin
synthesis.
It is acidic and has an n-octanol:phosphate buffer
partition coefficient of 0.5 at pH
7.4.
Pharmacokinetics
After oral administration,
approximately 80% of a radiolabelled dose of nabumetone is found
in the urine, indicating that nabumetone is well absorbed from the
gastrointestinal
tract. Nabumetone itself is not detected in the plasma
because, after absorption, it undergoes rapid biotransformation
to the principal active
metabolite, 6-methoxy-2-naphthylacetic acid
(6MNA). Approximately 35% of a 1000 mg
oral dose
of nabumetone is converted to 6MNA and 50% is converted into unidentified
metabolites which are subsequently excreted in the urine. Following
oral administration
of nabumetone, 6MNA exhibits pharmacokinetic characteristics that
generally follow a one-compartment model with first order
input and first order
elimination.
6MNA is more than 99% bound
to plasma proteins. The
free fraction is dependent
on total concentration
of 6MNA and is proportional to dose
over the range of 1000
mg to 2000 mg. It is 0.2%
to 0.3% at concentrations typically achieved following administration
of nabumetone 1000 mg and
is approximately 0.6% to 0.8% of the total concentrations at steady
state following daily
administration of 2000 mg.
Steady-state plasma
concentrations of 6MNA are slightly lower than predicted from single-dose
data. This may result from the higher fraction
of unbound 6MNA which undergoes greater hepatic
clearance.
Coadministration of food
increases the rate of absorption
and subsequent appearance of 6MNA in the plasma
but does not affect the
extent of conversion of nabumetone into 6MNA. Peak plasma
concentrations of 6MNA are increased by approximately one third.
Coadministration with an aluminum-containing antacid
had no significant effect on the bioavailability of 6MNA.
| TABLE 1 Mean pharmacokinetic parameters
of nabumetone active metabolite
(6MNA) at steady state
following oral administration
of 1000 mg or 2000
mg doses of Nabumetone |
| |
Young Adults Mean (±)
SD |
Young Adults Mean (±)
SD |
Elderly Mean (±)
SD |
| Abbreviations |
1000 mg |
2000 mg |
1000 mg |
| (units) |
n = 31 |
n = 12 |
n = 27 |
| tmax (hours) |
3.0(1.0 to 12.0) |
2.5(1.0 to 8.0) |
4.0(1.0 to 10.0) |
| t1/2 (hours) |
22.5 ± 3.7 |
26.2 ± 3.7 |
29.8 ± 8.1 |
| Clss/F (ml/min) |
26.1 ± 17.3 |
21.0 ± 4.0 |
18.6 ± 13.4 |
| Vdss/F (l) |
55.4 ± 26.4 |
53.4 ± 11.3 |
50.2 ± 25.3 |
6MNA undergoes biotransformation
in the liver, producing inactive metabolites that are eliminated
as both free metabolites and conjugates. None of the known metabolites
of 6MNA has been detected in plasma. Preliminary in vivo
and in vitro studies suggests that unlike other NSAIDs, there
is no evidence of enterohepatic
recirculation of the active metabolite. Approximately 75% of a radiolabelled
dose was recovered in urine
in 48 hours. Approximately 80% was recovered in 168 hours. A further
9% appeared in the feces. In
the first 48 hours, metabolites consisted of (TABLE 2):
| TABLE 2 |
| -nabumetone, unchanged |
not detectable |
| -6-methoxy-2-naphthylacetic acid
(6MNA), unchanged |
< 1% |
| -6MNA, conjugated |
11% |
| -6-hydroxy-2-naphthylacetic acid
(6HNA), unchanged |
5% |
| -6HNA, conjugated |
7% |
| -4-(6-hydroxy-2-naphthyl)-butan-2-ol,
conjugated |
9% |
| -O-desmethyl-nabumetone, conjugated |
7% |
| -unidentified minor
metabolites |
34% |
| Total % Dose: |
73% |
Following oral administration
of dosages of 1000 mg to
2000 mg to steady state,
the mean plasma
clearance of 6MNA
is 20 to 30 ml/min, and the elimination half-life is approximately
24 hours.
Elderly Patients: Steady-state plasma
concentrations in elderly patients were generally higher than in
young healthy subjects. (See TABLE 1 for summary of pharmacokinetic
parameters.)
Renal Insufficiency: In
studies of patients with renal insufficiency, the mean
terminal half-life
of 6MNA was increased in patients with severe renal
dysfunction (creatinine
clearance <30 ml/min./1.73m2).
In patients undergoing hemodialysis, steady-state plasma
concentrations of the active metabolite
were similar to those observed in healthy subjects. Due to extensive
protein-binding, 6MNA is not dialyzable.
Hepatic Impairment: Data in patients with severe
hepatic impairment are limited. Biotransformation of nabumetone
to 6MNA and further metabolism of 6MNA to inactive metabolites is
dependent on hepatic
function and could be reduced in patients with severe hepatic
impairment (history
of or biopsy-proven cirrhosis).
Special Studies
Gastrointestinal: Nabumetone was compared to aspirin
in inducing gastrointestinal
blood loss. Food intake
was not monitored. Studies utilizing51Cr-tagged red
blood cells in healthy
males showed no difference in fecal blood
loss after 3 or 4 weeks
administration
of nabumetone 1000 mg or
2000 mg daily when compared
to either placebo-treated or nontreated subjects. In
contrast, aspirin 3600
mg daily produced an increase
in fecal blood loss
when compared to the nabumetone-treated, placebo-treated or nontreated
subjects. The clinical
relevance of the data is unknown.
The following endoscopy trials entered patients who had been previously
treated with NSAIDs. These patients had varying baseline
scores and different courses of treatment. The trials were not designed
to correlate symptoms and endoscopy scores. The clinical
relevance of these endoscopy trials, i.e., either G.I. symptoms
or serious G.I events, is not known.
Ten endoscopy studies were conducted in 488 patients who had baseline
and post-treatment endoscopy. In
5 clinical trials that
compared a total of 194 patients on nabumetone 1000 mg
daily or naproxen 250 mg
or 500 mg twice daily for 3 to 12 weeks. Nabumetone treatment
resulted in fewer patients with endoscopically detected lesions
(>3 mm). In 2 trials a
total of 101 patients on nabumetone 1000 mg
or 2000 mg daily or piroxicam
10 mg to 20 mg for 7 to 10
days, there were fewer nabumetone patients with endoscopically detected
lesions. In 3 trials of a
total of 47 patients on nabumetone 1000 mg daily or indomethacin
100 mg to 150 mg
daily for 3 to 4 weeks, the endoscopy scores were higher with indomethacin.
Another 12-week trial in a total of 171 patients compared the results
of treatment with
nabumetone 1000 mg/day to ibuprofen
2400 mg/day and ibuprofen
2400 mg/day plus misoprostol 800 mcg/day. The results showed that
patients treated with nabumetone had a lower number
of endoscopically detected lesions (>5 mm) than patients treated
with ibuprofen alone
but comparable to the combination of ibuprofen plus misoprostol.
The results did not correlate with abdominal
pain.
Other: In
1-week repeat-dose studies in healthy volunteers, nabumetone 1000
mg daily had little effect
on collagen-induced platelet aggregation and no effect
on bleeding time. In
comparison, naproxen 500 mg daily suppressed collagen-induced platelet
aggregation and
significantly increased bleeding
time.
CLINICAL STUDIES
Osteoarthritis: The use of nabumetone in relieving
the signs and symptoms of osteoarthritis
was assessed in double-blind controlled trials in which 1047 patients
were treated for 6 weeks to 6 months. In these trials, nabumetone
in a dose of 1000 mg/day
administered at night was comparable to naproxen 500 mg/day and
to aspirin 3600 mg/day.
Rheumatoid Arthritis: The use of nabumetone in relieving
the signs and symptoms of rheumatoid
arthritis was assessed
in double-blind, randomized, controlled trials in which 770 patients
were treated for 3 weeks to 6 months. Nabumetone, in a dose
of 1000 mg/day administered at night was comparable to naproxen
500 mg/day and to aspirin
3600 mg/day.
In controlled clinical
trials of rheumatoid
arthritis patients,
nabumetone has been used in combination with gold, d-penicillamine
and corticosteroids.
Individualization Of Dosing: There is considerable
interpatient variation in response
to nabumetone. Therapy is usually initiated at a nabumetone dose
of 1000 mg daily, then adjusted,
if needed, based on clinical response.
In clinical trials
with osteoarthritis
and rheumatoid arthritis
patients, most patients responded to nabumetone in doses of 1000
mg/day administered nightly: total daily dosages up to 2000 mg
were used. In open-labelled
studies, 1490 patients were permitted dosage
increases and were followed for approximately 1 year (mode). Twenty
percent of patients
(n=294) were withdrawn for lack of effectiveness
during the first year of these open-labelled studies. The following
table (TABLE 3) provides
patient-exposure to doses used in the U.S. clinical
trials:
| TABLE 3 Clinical double-blind
and open-labelled trials of Nabumetone in osteoarthritis
and rheumatoid
arthritis |
| |
Number of Patients |
Mean/Mode Duration of Treatment (yrs.) |
|
Nabumetone Dose
|
OA |
RA |
OA |
RA |
|
500 mg
|
17 |
6 |
0.4/- |
0.2/- |
|
1000 mg
|
917 |
701 |
1.2/1 |
1.4/1 |
|
1500 mg
|
645 |
224 |
2.3/1 |
1.7/1 |
|
2000 mg
|
15 |
100 |
0.6/1 |
1.3/1 |
As with other NSAIDs, the lowest dose
should be sought for each patient. Patients weighing under 50 kg
may be less likely to require dosages beyond 1000 mg. Therefore,
after observing the response
to initial therapy,
the dose should be adjusted to meet individual patients' requirements.
top
