British Journal of Rheumatology 1996;35(suppl.

1): 13-16

A REVIEW OF THE CLINICAL PHARMACOKINETICS OF MELOXICAM

D. TURCK, W. ROTH and U. BUSCH
Department of Pharmacokinetics and Drug Metabolism, Dr Karl Thomae GmbH, Birkendorfer Strafie 65.88397
BiberachJRiss, Germany

SUMMARY
Meloxicam is a new preferential cvclooxygenase-2 (COX-2) inhibitor currently for the treatment of osteoarthritis and rheumatoid
arthritis. Its pharmacokinetic profile is characterized by a prolonged and almost complete absorption and the drug is >99.5%
bound to plasma proteins. Meloxicam is metabolized to four biologically inactive main metabolites, which are excreted in both urine
and faeces. The elimination half-life (fa) of meloxicam is ~20 h. This isreflectedin a total plasma clearance (CL) of 0.42 - 0.481/h.
Steady-state plasma concentrations are achieved within 3-5 days. The pharmacokinetic parameters of meloxicam are linear over
the dose range 7.5-30 mg and bioequrvalence has been shown for a number of different formulations. No interactions were
observed following the concomitant administration of food, cimetidine, antacid, aspirin, fJ-acetyldigoxin, methotrexate, warfarin or
furosemide. Neither hepatic insufficiency nor moderate renal dysfunction have any relevant effects on the pharmacokinetics of
meloxicam and dosage adjustments in the elderly are not required.
KEY WORDS: Meloxicam, Pharmacokinetic properties, Absorption, Distribution, Metabolism, Elimination, Interactions.

MELOXICAM [4-hydroxy-2-mcthyl-iV-(5-methyl-2-thia- concentrations (Cmax) were achieved after 5-6 h (fmax)

zolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 -di-
oxide; UHAC 62 XX, Boehringer Ingelheim], is a new
enolic acid class non-steroidal anti-inflammatory drug
(NSAID). Meloxicam's good tolerability, particularly in
the gastrointestinal tract [1], is believed to be due to its
preferential inhibition of inducible cyclooxygenase-2
(COX-2, involved in inflammatory processes) over
COX-1, which has a physiological function [2]. In this
review, the clinical pharmacokinetic properties of
meloxicam are summarized.
PATIENTS AND METHODS
The phannacokinetic characteristics of meloxicam
have been extensively investigated and complete plasma
concentration-time profiles have been obtained from
>400 male and female volunteers as well as in a number
of special patient groups (hepatic insufficiency, elderly,
renal insufficiency). Meloxicam was administered either
as an intravenous or intramuscular solution as well as
by oral capsule or tablet, or rectally as a suppository.
Drug plasma concentrations were quantified by means
of specific and validated high performance liquid
chromatography assays. Pharmacokinetic parameters
were calculated using standard non-compartmental
analyses.
when administered after breakfast [4]. The onset of
uvuun of meloxicam occurs much earlier than tmax- The
Cmax occurred later (/max was doubled) when meloxi-
cam was administered in a fasted state. During chronic
therapy for osteoarthritis or rheumatoid arthritis it is
generally more common to administer NSAIDs after a
meal, thus the tmaxjs value of 5-6 h for meloxicam is
probably the clinically more relevant value. Very similar
values were found after rectal administration [3].
Absorption after intramuscular injection is faster than
after oral administration, with Cmax occurring after
1-1.5 h [5]. Ninety per cent of the Cmax is achieved after
0.87 h [5].
Mean plasma concentration-time profiles at steady
state are shown in Fig. 1. Multiple concentration peaks
are evident in profiles from individual volunteers which
indicate a continual absorption for several hours after
2.0-

PHARMACOKINETIC PROPERTIES i 1.5-

Absorption
The absorption of meloxicam has been investigated 0.5-
following administration of intramuscular solutions,
oral capsules or tablets, and rectal suppositories. The 0.0'
144 150 156 162 168 174 160 168 192
absolute bioavailability (F) was 89% [3] for oral capsules
tlms [houni]
after a single 30 mg dose. Maximum meloxicam plasma

Correspondence to: Dr D. Tfirck, Department of Pharmaco-

kinetka and Drug Metabolism, Dr Karl Thomae GmbH, Birkendorfer Fio. 1.—Mean plasma concentration-time profiles of meloxicam 7.5
Strafie 65, D-88397 Biberach/Riss, Germany or IS mg administered either as a capsule or tablet

O 1996 British Society for Rheumatology

13
14 STUDIES ON MELOXICAM (MOBIQ

the Cmax has been attained. Similar observations with
other drugs of this class suggest a recirculation of the
drug in the gastrointestinal tract [6, 7]. NSAJDs
secreted in the intestinal lumen can be sequestered from
the intestine by means of repeated administration of
cholestyramine [6, 7]. For meloxicam, this results in a
50% increase in apparent clearance [8]. This suggests
meloxicam undergoes gastrointestinal recycling and
may account for why the drug does not undergo faster
elimination. In the case of possible meloxicam
overdosage it may be advantageous to administer
cholestyramine or charcoal [9], thereby eliciting a faster
elimination of the drug.
The absorption of meloxicam is independent of dose
over the range 7.5-30 mg, leading to dose-linear
increases in meloxicam plasma concentrations [3]. This
enables easy dose titration in those patients requiring
higher or lower doses than normal. A summary of
typical pharmacokinetic parameters of meloxicam after
single and multiple doses is listed in Table I.
Distribution
Most NSAIDs are highly protein bound to albumin
[10]; meloxicam is no exception, being >99% bound [3].
The binding is consistent over the concentration range
encountered in clinical practice. This high protein
binding results in a restricted volume of distribution
(Vd) of 10-15 1 [3], which is similar to that reported for
other NSAIDs [11]. Animal experiments suggest that
meloxicam is predominantly distributed to highly
perfused (albumin rich) compartments such as the
blood, liver, kidney, etc. [12]. The V<j equates approxi-
mately with the extracellular space, although meloxicam
readily penetrates other tissues. For example, 40-45% of
the accompanying steady-state meloxicam plasma
concentrations are found in synovial fluid, slightly
lower concentrations being observed in the adjacent
tissues [13]. Inflamed tissue is characterized by
extravasation and probably, decreased pH values,
compared with non-inflamed tissue. Such conditions
are ideally suited to 'trap' a NSAID from the
circulation. Indeed, high concentrations of meloxicam
in inflamed tissue have been observed in animal models
[14].
Metabolism
Meloxicam is almost exclusively eliminated by
metabolic degradation. The drug undergoes roughly
equal renal and faecal elimination, with <0.25%
excreted unchanged in urine and 1.6% of the parent
compound present in the faeces. The latter may also
represent a small amount of unabsorbed drug [15].
Mctabolically, meloxicam undergoes extensive phase I
reactions, and no conjugated derivatives have been
detected. The main metabolites are formed by oxidation
of the methyl group of the thiazolyl moiety; further
metabolites result from a cleavage of the thiazine ring
system (Fig. 2). The metabolism of meloxicam is largely
mediated through cytochrome P450 2C, most probably
on the isoenzyme 2C9. The four main metabolites of
meloxicam (AF-UH 1 SE, UH-AC 110 SE, BIBO 8032
and DS-AC 2 SE) have no biological activity [15].
Elimination
Oral meloxicam has a total clearance of 0.42-0.48 1/h
and an elimination half-life (ty,) of ~20 h [3].
Steady-state plasma concentrations are achieved within
3-5 days. In common with most other NSAIDs, a
considerable variation between subjects (interindividual
coefficient of variation 30%) has been observed.
In comparison with other NSAIDs of the same class,
meloxicam has a relatively short elimination half-life of
~20 h. This value allows a once-a-day dosage without
the need for a slow release formulation. The values for
piroxicam are ~53 h [16] and for tenoxicam -65-70 h
[17]. Additionally, steady state is achieved within 3-5

TABLE I
Summary of the mean pharmacokinetic parameters of meloxicam
Daily dose (mg) Formulation n Cmtx (mg/1) W(h) AUC(mgh/l) Cl(ml/min) Status
Single doses
15 Capsule 24 0.933 6.0 28.8 9.36 • Fed
15 Capsule 16 0.928 8.8 34.1 7.84 20.6 Fasted
30 Intravenous 12 - _ 76.9 7.15 20.0 Fasted
30 Capsule 12 1.72 8.7 67.5 8.15 22.0 Fasted
30 Capsule 6 1.51 10.7 66.5 8.54 24.3 Fasted
15 Suppository 24 0.952 5.0 24.0 11.70 * Fed
Multiple doses
7.5 Capsule 18 0.88 5.1 13.9 9.81 20.4 Fed
7.5 Capsule 27 1.03 5.6 17.6 7.73 22.5 Fed
7.5 Tablet 18 1.05 4.9 15.4 8.81 20.1 Fed
15 Capsule 18 1.92 5.6 30.0 8.95 22.2 Fed
15 Capsule 24 1.88 6.5 33.3 8.27 * Fed
15 Capsule 24 2.32 5.1 36.2 7.57 * Fed
15 Tablet 24 2.45 5.0 38.1 7.19 * Fed
7.5 Suppository 27 0.% 4.4 15.5 8.80 21.6 Fed
15 Suppository 24 1.72 5.4 29.3 9.86 * Fed
Abbreviations: Cm»x = maximum plasma concentrations; = time to Cnaxi AUC = area under plasma concentration-time curve; Ci =
clearance; ty, = elimination half life.
•Insufficient data points in the terminal phase.
 TURCK ETAL: CLINICAL PHARMACOKINETICS OF MELOXICAM
OH
Meloxicam not detected
AF-UH 1 SE (9%) UH-AC110SE(60%)
I4
Fio. 2.—Metabolic fate of meloxicam. "Site of
days with meloxicam whereas 1-2 weeks is necessary for
the other NSAIDs.
NSAIDs with a short elimination half-life, such as
diclofenac (t>/, 1-2 h [18]) need a slow release
formulation for a once-daily regimen. The performance
of slow release formulations may be influenced by the
concomitant intake of food. Diclofenac is a well known
example for which quite different concentration-time
profiles are seen with and without food [19]. Such food
effects are more rare with compounds with a longer
elimination half-life.
Interactions
The concomitant administration of food as well as
other agents is known to affect the absorption, as well
as elimination, of NSAIDs. Thus several pharma-
cokinetifr interaction trials involving meloxicam have
been undertaken which demonstrated the lack of
clinically relevant interactions with high-fat food [4],
P-acetyldigoxin [20], methotrexate [21], cimetidine [22],
antacids [22], acetylsalicylic acid [22] or furosemide [23].
Recent data also indicate that there is no relevant
interaction with warfarin.
Effects of disease states or age on pharmacokinetics
Excretory functions can be altered by increased age
and this may result in drug accumulation. This situation
has been reported for some other NSAIDs [24]. Patients
suffering from osteoarthritis are often elderly,
consequently the pharmacokinetics of meloxicam have
been evaluated in elderly arthritic patients. Interestingly,
there was no difference in pharmacokinetic parameters
between young (£55 yr) and elderly (>65 yr) male
patients; however, a 50% increase of meloxicam plasma
concentrations in elderly female patients (>65 yr) was
noted when compared with young female patients (£55
yr) [25]. This finding was confirmed by applying
population kinetic approaches to plasma samples from
several hundred patients, although the difference was
somewhat smaller (33% increase in the elderly female
[data on file, Boehringer Ingelhcim]). However, the
15
DS-AC2SE(16%)
HO
BIBO 8032 (4%)
incidence of adverse events in elderly females was not
higher compared with younger females. Thus the
increase does not warrant a dose adjustment. Similar
findings have been reported for the structurally related
NSAID, piroxicam [26].
The pharmacokinetics of NSAIDs may be affected
by hepatic or renal insufficiency. In summary, for
meloxicam there was no relevant influence of hepatic
insufficiency or mild-to-moderate renal dysfunction on
the drug's pharmacokinetics [27, 28]. Renal failure was
associated with reduced total meloxicam plasma
concentrations. However, an increase in the free fraction
compensated for this effect. Free area under the plasma
concentration-time curve values were very similar for
both renal failure patients and healthy subjects. Free
Cmax values tended to be increased in the renal failure
patients. As a safety precaution, the lower dose of
7.5 mg is recommended for patients with end-stage
renal failure.
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