CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of action of meloxicam, like that of other NSAIDs,
may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition
which is involved in the initial steps of the arachidonic acid cascade,
resulting in the reduced formation of prostaglandins, thromboxanes
and prostacylin. It is not completely understood how reduced synthesis
of these compounds results in therapeutic efficacy.
Pharmacodynamics
Meloxicam exhibits anti-inflammatory, analgesic, and antipyretic
activities.
Pharmacokinetics
Absorption
The absolute bioavailability
of meloxicam capsules was 89% following a single oral dose of 30 mg
compared with 30 mg IV bolus injection. Following single intravenous
doses, dose-proportional pharmacokinetics were shown in the range
of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of
meloxicam capsules were dose-proportional over the range of 7.5 mg
to 15 mg. Mean Cmax was achieved within four
to five hours after a 7.5 mg meloxicam tablet was taken under fasted
conditions, indicating a prolonged drug absorption. With multiple
dosing, steady-state concentrations were reached by Day 5. A second
meloxicam concentration peak occurs around 12 to 14 hours post-dose
suggesting biliary recycling.
Meloxicam oral suspension doses of 7.5 mg/5 mL and 15 mg/10 mL have
been found to be bioequivalent to meloxicam 7.5 mg and 15 mg capsules,
respectively. Meloxicam capsules have been shown to be bioequivalent
to MOBIC tablets.
Table 3 Single Dose and Steady-State Pharmacokinetic Parameters
for Oral 7.5 mg and 15 mg Meloxicam (Mean and % CV)1
|
|
Steady
State
|
Single
Dose
|
Pharmacokinetic Parameters (% CV)
|
Healthy male adults (Fed)2
|
Elderly males (Fed)2
|
Elderly females
(Fed)2
|
Renal failure (Fasted)
|
Hepatic insufficiency
(Fasted)
|
|
|
7.5 mg3 tablets
|
15 mg capsules
|
15 mg capsules
|
15 mg capsules
|
15 mg capsules
|
N
|
18
|
5
|
8
|
12
|
12
|
1
The parameter values in the table are from various studies
2
not
under high fat conditions
3
MOBIC tablets
4
Vz/f =Dose/(AUC•Kel) |
Cmax
|
[µg/mL] |
1.05 (20) |
2.3 (59) |
3.2 (24) |
0.59 (36) |
0.84 (29) |
tmax
|
[h] |
4.9 (8) |
5 (12) |
6 (27) |
4 (65) |
10 (87) |
t1/2
|
[h] |
20.1 (29) |
21 (34) |
24 (34) |
18 (46) |
16 (29) |
CL/f |
[mL/min] |
8.8 (29) |
9.9 (76) |
5.1 (22) |
19 (43) |
11 (44) |
Vz/f4
|
[L] |
14.7 (32) |
15 (42) |
10 (30) |
26 (44) |
14 (29) |
Food and AntacidEffects
Administration
of meloxicam capsules following a high fat breakfast (75 g of fat)
resulted in mean peak drug levels (i.e., Cmax) being increased by approximately 22% while the extent of absorption
(AUC) was unchanged. The time to maximum concentration (Tmax) was achieved between 5 and 6 hours. In comparison,
neither the AUC nor the Cmax values for meloxicam
suspension were affected following a similar high fat meal, while
mean Tmax values were increased to approximately
7 hours. No pharmacokinetic interaction was detected with concomitant
administration of antacids. Based on these results, MOBIC can be administered
without regard to timing of meals or concomitant administration of
antacids.
Distribution
The mean volume of
distribution (Vss) of meloxicam is approximately 10 L. Meloxicam is
~99.4% bound to human plasma proteins (primarily albumin) within the
therapeutic dose range. The fraction of protein binding is independent
of drug concentration, over the clinically relevant concentration
range, but decreases to ~99% in patients with renal disease. Meloxicam
penetration into human red blood cells, after oral dosing, is less
than 10%. Following a radiolabeled dose, over 90% of the radioactivity
detected in the plasma was present as unchanged meloxicam.
Meloxicam concentrations in synovial fluid,
after a single oral dose, range from 40% to 50% of those in plasma.
The free fraction in synovial fluid is 2.5 times higher than in plasma,
due to the lower albumin content in synovial fluid as compared to
plasma. The significance of this penetration is unknown.
Metabolism
Meloxicam is extensively
metabolized in the liver. Meloxicam metabolites include 5'-carboxy
meloxicam (60% of dose), from P-450 mediated metabolism formed by
oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam
which is also excreted to a lesser extent (9% of dose). In
vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing
enzyme) plays an important role in this metabolic pathway with a minor
contribution of the CYP3A4 isozyme. Patients’ peroxidase activity
is probably responsible for the other two metabolites which account
for 16% and 4% of the administered dose, respectively. All the four
metabolites are not known to have any in vivo pharmacological
activity.
Excretion
Meloxicam excretion
is predominantly in the form of metabolites, and occurs to equal extents
in the urine and feces. Only traces of the unchanged parent compound
are excreted in the urine (0.2%) and feces (1.6%). The extent of
the urinary excretion was confirmed for unlabeled multiple 7.5 mg
doses: 0.5%, 6%, and 13% of the dose were found in urine in the form
of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites,
respectively. There is significant biliary and/or enteral secretion
of the drug. This was demonstrated when oral administration of cholestyramine
following a single IV dose of meloxicam decreased the AUC of meloxicam
by 50%.
The mean elimination
half-life (t1/2) ranges from 15 hours to 20
hours. The elimination half-life is constant across dose levels indicating
linear metabolism within the therapeutic dose range. Plasma clearance
ranges from 7 to 9 mL/min.
Special Populations
Pediatric
After single (0.25 mg/kg) dose administration and after achieving
steady state (0.375 mg/kg/day), there was a general trend of approximately
30% lower exposure in younger patients (2 to 6 years old) as compared
to the older patients (7 to 16 years old). The older patients had
meloxicam exposures similar (single dose) or slightly reduced (steady
state) to those in the adult patients, when using AUC values normalized
to a dose of 0.25 mg/kg [
see Dosage and Administration
]. The meloxicam
mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0)
for the 2 to 6 year old patients, and 7 to 16 year old patients, respectively.
In a covariate analysis, utilizing population
pharmacokinetics body-weight, but not age, was the single predictive
covariate for differences in the meloxicam apparent oral plasma clearance.
The body-weight normalized apparent oral clearance values were adequate
predictors of meloxicam exposure in pediatric patients.
The pharmacokinetics of MOBIC in pediatric
patients under 2 years of age have not been investigated.
Geriatric
Elderly males (≥65 years of age) exhibited meloxicam plasma concentrations
and steady-state pharmacokinetics similar to young males. Elderly
females (≥65 years of age) had a 47% higher AUCss and 32% higher Cmax,ss as compared to younger
females (≤55 years of age) after body weight normalization. Despite
the increased total concentrations in the elderly females, the adverse
event profile was comparable for both elderly patient populations.
A smaller free fraction was found in elderly female patients in comparison
to elderly male patients.
Gender
Young females exhibited slightly lower plasma concentrations relative
to young males. After single doses of 7.5 mg MOBIC, the mean elimination
half-life was 19.5 hours for the female group as compared to 23.4
hours for the male group. At steady state, the data were similar
(17.9 hours vs 21.4 hours). This pharmacokinetic difference due to
gender is likely to be of little clinical importance. There was linearity
of pharmacokinetics and no appreciable difference in the Cmax or Tmax across genders.
Hepatic Impairment
Following a single 15 mg dose of meloxicam there was
no marked difference in plasma concentrations in patients with mild
(Child-Pugh Class I) or moderate (Child-Pugh Class II) hepatic impairment
compared to healthy volunteers. Protein binding of meloxicam was
not affected by hepatic impairment. No dosage adjustment is necessary
in patients with mild to moderate hepatic impairment. Patients with
severe hepatic impairment (Child-Pugh Class III) have not been adequately
studied [
see Warnings and Precautions and Use in Specific Populations
].
Renal Impairment
Meloxicam pharmacokinetics have been investigated in
subjects with mild and moderate renal impairment. Total drug plasma
concentrations of meloxicam decreased and total clearance of meloxicam
increased with the degree of renal impairment while free AUC values
were similar in all groups. The higher meloxicam clearance in subjects
with renal impairment may be due to increased fraction of unbound
meloxicam which is available for hepatic metabolism and subsequent
excretion. No dosage adjustment is necessary in patients with mild
to moderate renal impairment. Patients with severe renal impairment
have not been adequately studied. The use of MOBIC in subjects with
severe renal impairment is not recommended [
see
Warnings and Precautions and
Use in Specific Populations
].
Hemodialysis
Following a single dose of meloxicam, the free Cmax plasma concentrations were higher in patients with renal failure
on chronic hemodialysis (1% free fraction) in comparison to healthy
volunteers (0.3% free fraction). Hemodialysis did not lower the total
drug concentration in plasma; therefore, additional doses are not
necessary after hemodialysis. Meloxicam is not dialyzable [
see Dosage and Administration , Warnings and Precautions , and Use in Specific Populations
].
Drug Interactions
Aspirin:
When MOBIC is administered with aspirin
(1000 mg three times daily) to healthy volunteers, it tended to increase
the AUC (10%) and Cmax (24%) of meloxicam.
The clinical significance of this interaction is not known [
see Drug Interactions
].
Cholestyramine:
Pretreatment for four
days with cholestyramine significantly increased the clearance of
meloxicam by 50%. This resulted in a decrease in t1/2, from 19.2 hours to 12.5 hours, and a 35% reduction in AUC. This
suggests the existence of a recirculation pathway for meloxicam in
the gastrointestinal tract. The clinical relevance of this interaction
has not been established.
Cimetidine:
Concomitant administration
of 200 mg cimetidine four times daily did not alter the single-dose
pharmacokinetics of 30 mg meloxicam.
Digoxin:
Meloxicam 15 mg once
daily for 7 days did not alter the plasma concentration profile of
digoxin after β-acetyldigoxin administration for 7 days at clinical
doses. In vitro testing found no protein binding
drug interaction between digoxin and meloxicam.
Lithium:
In a
study conducted in healthy subjects, mean pre-dose lithium concentration
and AUC were increased by 21% in subjects receiving lithium doses
ranging from 804 to 1072 mg twice daily with meloxicam 15 mg QD every
day as compared to subjects receiving lithium alone [
see Drug Interactions
].
Methotrexate:
A study in 13 rheumatoid arthritis
(RA) patients evaluated the effects of multiple doses of meloxicam
on the pharmacokinetics of methotrexate taken once weekly. Meloxicam
did not have a significant effect on the pharmacokinetics of single
doses of methotrexate. In vitro, methotrexate did
not displace meloxicam from its human serum binding sites [
see Drug Interactions
].
Warfarin:
The effect of meloxicam on
the anticoagulant effect of warfarin was studied in a group of healthy
subjects receiving daily doses of warfarin that produced an INR (International
Normalized Ratio) between 1.2 and 1.8. In these subjects, meloxicam
did not alter warfarin pharmacokinetics and the average anticoagulant
effect of warfarin as determined by prothrombin time. However, one
subject showed an increase in INR from 1.5 to 2.1. Caution should
be used when administering MOBIC with warfarin since patients on warfarin
may experience changes in INR and an increased risk of bleeding complications
when a new medication is introduced [
see Drug Interactions
].
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: There
was no increase in tumor incidence in long-term carcinogenicity studies
in rats (104 weeks) and mice (99 weeks) administered meloxicam at
oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in
mice (up to 0.5- and 2.6-fold, respectively, the maximum recommended
human daily dose based on body surface area comparison).
Mutagenesis: Meloxicam
was not mutagenic in an Ames assay, or clastogenic in a chromosome
aberration assay with human lymphocytes and an in vivo micronucleus test in mouse bone marrow.
Impairment of Fertility: Meloxicam
did not impair male and female fertility in rats at oral doses up
to 9 mg/kg/day in males and 5 mg/kg/day in females (up to 5.8- and
3.2-fold greater, respectively, than the maximum recommended human
daily dose based on body surface area comparison).
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