Celebrex is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Celebrex is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, Celebrex does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
Platelets
In
clinical
trials
using
normal
volunteers,
Celebrex
at
single
doses up
to 800
mg and
multiple
doses of
600 mg
twice
daily
for up
to 7
days
duration
(higher
than
recommended
therapeutic
doses)
had no
effect
on
reduction
of
platelet
aggregation
or
increase
in
bleeding
time.
Because
of its
lack of
platelet
effects,
Celebrex
is not a
substitute
for
aspirin
for
cardiovascular
prophylaxis.
It is
not
known if
there
are any
effects
of
Celebrex
on
platelets
that may
contribute
to the
increased
risk of
serious
cardiovascular
thrombotic
adverse
events
associated
with the
use of
Celebrex.
Fluid
Retention
Inhibition
of PGE2
synthesis
may lead
to
sodium
and
water
retention
through
increased
reabsorption
in the
renal
medullary
thick
ascending
loop of
Henle
and
perhaps
other
segments
of the
distal
nephron.
In the
collecting
ducts,
PGE2
appears
to
inhibit
water
reabsorption
by
counteracting
the
action
of
antidiuretic
hormone.
Pharmacokinetics
-
Absorption
Peak
plasma
levels
of
celecoxib
occur
approximately
3 hrs
after an
oral
dose.
Under
fasting
conditions,
both
peak
plasma
levels (Cmax)
and area
under
the
curve (AUC)
are
roughly
dose
proportional
up to
200 mg
BID; at
higher
doses
there
are less
than
proportional
increases
in Cmax
and AUC
(see
Food
Effects).
Absolute
bioavailability
studies
have not
been
conducted.
With
multiple
dosing,
steady
state
conditions
are
reached
on or
before
Day 5.
The
pharmacokinetic
parameters
of
celecoxib
in a
group of
healthy
subjects
are
shown in
Table 1.
Summary
of
Single
Dose
(200 mg)
Disposition
Kinetics
of
Celecoxib
in
Healthy
Subjects
|
Mean (%CV) PK Parameter Values |
||||
|
Cmax, ng/mL |
Tmax, hr |
Effective t˝, hr |
VSS/F,L |
CL/F, L/hr |
|
705 (38) |
2.8 (37) |
11.2 (31) |
429 (34) |
27.7 (28) |
|
1 Subjects under fasting conditions (n=36, 19-52 yrs.) |
||||
Food Effects
When Celebrex capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Coadministration of Celebrex with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. Celebrex, at doses up to 200 mg BID can be administered without regard to timing of meals. Higher doses (400 mg BID) should be administered with food to improve absorption.
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in Cmax, Tmax or t˝ after administration of capsule contents on applesauce.
Distribution
In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. In vitro studies indicate that celecoxib binds primarily to albumin and, to a lesser extent α1-acid glycoprotein. The apparent volume of distribution at steady state (VSS/F) is approximately 400 L suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.
Metabolism
Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors. Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.
Excretion
Celecoxib is eliminated predominantly by hepatic metabolism with little (< 3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was excreted in the feces and 27% was excreted into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t˝) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.
Special Populations
Geriatric
At steady state, elderly subjects (over 65 years old) had a 40% higher Cmax and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight initiate therapy at the lowest recommended dose.
Pediatric
The steady state pharmacokinetics of celecoxib administered as an investigational oral suspension was evaluated in 152 juvenile rheumatoid arthritis (JRA) patients 2 years to 17 years of age weighing ≥ 10 kg with pauciarticular or polyarticular course JRA and in patients with systemic onset JRA. Population pharmacokinetic analysis indicated that the oral clearance (unadjusted for body weight) of celecoxib increases less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient.
Twice-daily administration of 50 mg capsules to JRA patients weighing ≥ 12 to ≤ 25 kg and 100 mg capsules to JRA patients weighing > 25 kg should achieve plasma concentrations similar to those observed in a clinical trial