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Comparison of the ulcerogenic dose and the anti-inflammatory effective dose in the rat adjuvant arthritis confirmed the therapeutic margin in animals over standard NSAIDs.
In vivo, meloxicam inhibited prostaglandin biosynthesis more potently at the site of inflammation than in the gastric mucosa or the kidney.
These differences are thought to be related to a selective inhibition of COX-2 relative to COX-1 and it is believed that COX-2 inhibition provides the therapeutic effects of NSAIDs whereas inhibition of constitutive COX-1 may be responsible for gastric and renal side effects.
The COX-2 selectivity of meloxicam has been confirmed both in vitro and ex vivo in a number of test systems. In the human whole blood assay, meloxicam has been shown in vitro to inhibit COX-2 selectively. Meloxicam (7.5 and 15 mg) demonstrated a greater inhibition of COX-2 ex vivo, as demonstrated by a greater inhibition of lipopolysaccharide-stimulated PGE2 production (COX-2) as compared with thromboxane production in clotting blood (COX-1). These effects were dose-dependent. Meloxicam has been demonstrated to have no effect on either platelet aggregation or bleeding time at recommended doses ex vivo, while indomethacin, diclofenac, ibuprofen and naproxen significantly inhibited platelet aggregation and prolonged bleeding.
In clinical trials, gastrointestinal (GI) adverse events overall were reported less frequently with meloxicam 7.5 and 15 mg than with the NSAIDs with which it has been compared, due predominantly to a lower reporting incidence of events eg, dyspepsia, vomiting, nausea and abdominal pain. The incidence of upper GI perforation, ulcers and bleeds reported in association with meloxicam is low and dose-dependent.
There is no single study powered adequately to detect statistically differences in the incidence of clinically significant upper GI perforation, obstruction or bleeds between meloxicam and other NSAIDs. A pooled analysis has been conducted involving patients treated with meloxicam in 35 clinical trials in the indications osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Exposure to meloxicam in these trials ranged from 3 weeks-1year (most patients were enrolled in 1-month studies). Almost all patients participated in trials that permitted enrollment of patients with a prior history of GI perforation, ulcer or bleed.
The incidence of clinically significant upper GI perforation, obstruction or bleed (POB) was assessed retrospectively following independent blinded review of cases.
Results are shown in the table:
Click on icon to see table/diagram/imagePharmacokinetics: Absorption: Oral Administration: Meloxicam is well-absorbed from the GI tract, which is reflected by a high absolute bioavailability of 89% following oral administration.
Following single dose administration of meloxicam, mean maximum plasma concentrations are achieved within 5-6 hrs with solid oral dosage forms (tablets).
With multiple dosing, steady-state conditions were reached within 3-5 days. Once-daily dosing leads to drug plasma concentrations with a relatively small peak-trough fluctuation in the range of 0.4-1 mcg/mL for 7.5 mg doses and 0.8-2 mcg/mL for 15 mg doses, respectively (Cmin and Cmax at steady-state, correspondingly).
Maximum plasma concentrations of meloxicam at steady-state, are achieved within 5-6 hrs.
Extent of absorption for meloxicam following oral administration is not altered by concomitant food intake or the use of inorganic antacids. Dose linearity was demonstrated after oral administration in the therapeutic dose range of 7.5-15 mg.
Distribution: Meloxicam is very strongly bound to plasma proteins, essentially albumin (99%). Meloxicam penetrates into synovial fluid to give concentrations approximately half of those in plasma. Volume of distribution is low, on average 11 L. Interindividual variation is the order of 7-20%.
The volume of distribution following administration of mulitple oral doses of meloxicam (7.5-15 mg) is about 14-17 L with coefficients of variation ranging from 24-32%.
Biotransformation: Meloxicam undergoes extensive hepatic biotransformation. Four different metabolites of meloxicam were identified in urine, which are all pharmacodynamically inactive. The major metabolite, 5'-carboxymeloxicam (60% of dose), is formed by oxidation of an intermediate metabolite 5'-hydroxymethylmeloxicam, which is also excreted to a lesser extent (9% of dose). In vitro studies suggest that CYP2C9 plays an important role in this metabolic pathway, with a minor contribution from the CYP3A4 isoenzyme. The patient's peroxidase activity is probably responsible for the other 2 metabolites, which account for 16% and 4% of the administered dose, respectively.
Elimination: Meloxicam is excreted predominantly in the form of metabolites and occurs to equal extents in urine and faeces. Less than 5% of the daily dose is excreted unchanged in faeces, while only traces of the parent compound are excreted in urine.
The mean elimination half-life varies between 13 and 25 hrs after oral, IM and IV administration.
Total plasma clearance amounts about 7-12 mL/min following single doses orally, IV or rectally administered.
Linearity/Nonlinearity: Meloxicam demonstrates linear pharmacokinetics in the therapeutic dose range of 7.5-15 mg following per oral or IM administration.
Special Populations: Hepatic/Renal Insufficiency: Neither hepatic insufficiency, nor mild to moderate renal insufficiency have a substantial effect on meloxicam pharmacokinetics. In terminal renal failure, the increase in the volume of distribution may result in higher free meloxicam concentrations and a daily dose of 7.5 mg must not be exceeded.
Elderly: Elderly male subjects exhibited similar mean pharmacokinetic parameters but the elimination half-life is significantly longer compared to those of young male subjects. Elderly female patients showed higher AUC values and longer elimination half-lives compared to those of younger subjects of both genders. Mean plasma clearance at steady state in elderly subjects was slightly lower than that reported for younger subjects.
Children: In a study of 36 children, kinetic measurements were made in 18 children at doses of 0.25 mg/kg body weight. Maximum plasma concentration Cmax (-34%) as well as AUC0-∞ (-28%) tended to be lower in the younger age group (aged 2-6 years, n=7) as compared to the older age group (7-14 years, n=11) while weight normalized clearance appeared to be higher in the younger age group. A historical comparison with adults revealed that plasma concentrations were at least similar for older children and adults. Plasma elimination half-lives (13 hrs) were similar for both groups and tended to be shorter than in adults (15-20 hrs).
