A Review Of The Clinical Pharmacokinetics Of Meloxicam

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-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 -dioxide; 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.

concentrations (Cmax) were achieved after 5-6 h (fmax) when administered after breakfast [4]. The onset of uvuun of meloxicam occurs much earlier than tmax- The Cmax occurred later (/max was doubled) when meloxicam 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

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.

2.0-

i

PHARMACOKINETIC PROPERTIES Absorption The absorption of meloxicam has been investigated following administration of intramuscular solutions, oral capsules or tablets, and rectal suppositories. The absolute bioavailability (F) was 89% [3] for oral capsules after a single 30 mg dose. Maximum meloxicam plasma

1.5-

0.50.0' 144

150

156

162

168

174

160

168

192

tlms [houni]

Correspondence to: Dr D. Tfirck, Department of Pharmacokinetka and Drug Metabolism, Dr Karl Thomae GmbH, Birkendorfer Strafie 65, D-88397 Biberach/Riss, Germany

Fio. 1.—Mean plasma concentration-time profiles of meloxicam 7.5 or IS mg administered either as a capsule or tablet

O 1996 British Society for Rheumatology

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STUDIES ON MELOXICAM (MOBIQ

14

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.

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].

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 approximately 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

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 n

Cmtx (mg/1)

W(h)

AUC(mgh/l)

Cl(ml/min)

Capsule Capsule Intravenous Capsule Capsule Suppository

24 16 12 12 6 24

0.933 0.928 1.72 1.51 0.952

6.0 8.8 _ 8.7 5.0

28.8 34.1 76.9 67.5 66.5 24.0

9.36 7.84 7.15 8.15 8.54 11.70

Capsule Capsule Tablet Capsule Capsule Capsule Tablet Suppository Suppository

18 27 18 18 24 24 24 27 24

0.88 1.03 1.05 1.92 1.88 2.32 2.45 0.% 1.72

5.1 5.6 4.9 5.6 6.5 5.1 5.0 4.4 5.4

13.9 17.6 15.4 30.0 33.3 36.2 38.1 15.5 29.3

9.81 7.73 8.81 8.95 8.27 7.57 7.19 8.80 9.86

Daily dose (mg) Formulation Single doses 15 15 30 30 30 15 Multiple doses 7.5 7.5 7.5 15 15 15 15 7.5 15

Abbreviations: Cm»x = maximum plasma concentrations; clearance; ty, = elimination half life. •Insufficient data points in the terminal phase.

10.7

Status

•

Fed

20.6 20.0 22.0 24.3

Fasted Fasted Fasted Fasted

*

Fed

20.4 22.5 20.1 22.2

Fed Fed Fed Fed Fed Fed Fed Fed Fed

* * * 21.6

*

= time to Cnaxi AUC = area under plasma concentration-time curve; Ci =

TURCK ETAL: CLINICAL PHARMACOKINETICS OF MELOXICAM

15

OH

Meloxicam

not detected

DS-AC2SE(16%)

HO

AF-UH 1 SE (9%)

Fio. 2.—Metabolic fate of meloxicam. "Site of

UH-AC110SE(60%)

BIBO 8032 (4%)

I4

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 pharmacokinetifr 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

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. REFERENCES

1. Distel M, Bluhmki E. Global analysis of safety of meloxicam, a new enolic acid derived non-steroidal antiinflammatory agent. RheumatolEur 1995;24(suppl. 3):390. 2. Engelhardt G. Meloxicam a potent inhibitor of COX-2. Data presented at 9th International Conference on Prostaglandins and Related Compounds, Florence, Italy, June 6-10,1994, p. 82. 3. Turck D, Busch U, Heinzel G, Narjes H. Clinical pharmacokinetics of meloxicam. Eur J Rheumatol Inflamm 1995;15:22-34. 4. Tflrck D, Busch U, Heinzel G, Narjes H, Nehmiz G. Effect of food on the pharmacokinetics of meloxicam after oral administration. Clin Drug Invest 1995^:270-6. 5. Narjes H, Turck D, Busch U, Heinzel G, Nehmiz G. Tolerability and pharmacokinetics of meloxicam after i.m. administration. Br J Clin Pharmacol 1996;41:135-40. 6. Guentert TW, Defoin R, Mosberg H. The influence of cholcstyramine on the elimination of tenoxicam and piroxicam. Eur J Gin Pharmacol 1988^4:283-9. 7. Benveniste C, Striberni R, Dyer P. Indirect assessment of the enterohepatic recirculation of piroxicam and tenoxicam. Eur J Clin Pharmacol 199038:457-9.

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8. Busch H, Heinzel G, Narjes H. Effect of cholestyramine on pharmacokinctics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID) in man. 1st International Congress of Inflammation, Barcelona, Spain, June, 17-22,1990,283; Eur J Clin Pharmacol 1995;48:269-72. 9. Laufen H, Leitold M. The effect of activated charcoal on the bioavailability of piroxicam in man. Int J Clin Pharmacol Ther Toxicol 1986^4:48-52. 10. Lin JH, Cocchetto DM, Ehiggan DE. Protein binding as a primary determinant of the clinical phannacokinetic properties of nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1987;12:402-32. 11. Verbeeck RK, Loewen GR, Blackburn XL. Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs. Clin Pharmacokinet 1983;fc297-331. 12. Busch U. Pharmacokinetics of meloxicam in animals Scand J Rheumatol 1994;Snppl 98:abstract no. 119. 13. Degner F, Heinzel G, Busch U. Transsynovial kinetics of meloxicam. Scand J Rheumatol 1994;Snppl 9&abstract no. 121. 14. Busch U, Engelhardt G. Distribution of [14C]meloxicam in joints of rats with adjuvant arthritis. Drugs Exp Clin Res 1990;16:49-52. 15. Schmid J, Prox A, Busch U, Kaschke S, Sauter T. The biotransformation of meloxicam in man and rat Scand J Rheumatol 1994;Suppl 9fcabstract no. 118. 16. Hobbs DC. Piroxicam pharmacokinetics: recent clinical results relating kinetics and plasma levels to age, sex and adverse events. Am J Med 1986;81(suppl. 5B):22-8. 17. Nilsen OG. Clinical pharmacokinetics of tenoxicam. Clin Pharmacokinet 1994^6:16-43. 18. Wins JV, Kendall MJ, Flinn RM, Thomhill DP, Welling P. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol 1979;16:405-10. 19. Scheidel B, Blume H, Walter K, Stanislaus F, Babej-D611e RM. Bioavailability study of enteric coated diclofenac formulations/2nd communication: bioavailability study

following single dose administration of multiple unit formulation and a single unit formulation comparing fasted and non fasted conditions. Arzneimittelforschung 1993;43: 1211-5. 20. Degner F, Heinzel G, Narjes H, Tiirck D. The effect of meloxicam on the pharmacokinetics of (J-acetyldigoxin. Br J Clin Pharmacol 1995;40:486-8. 21. Hubner G, Sander O, Degner F, Rau R. Lack of phannacokinetic interaction of meloxicam with methotrexate in RA patients. Scand J Rheumatol 1994;Suppl 98abstract no. 108. 22. Busch U, Heinzel G, Narjes H, Nehmiz G. Investigation of interaction of meloxicam with cimetidine, Maalox® or aspirin. J Clin Pharmacol, in press. 23. Muller FO, Schall R, DeVaal AC, Groenewoud G, Hundt HKL, Middle MV. No interaction of meloxicam with either single or multiple repeated doses of furosemide. Eur J Clin Pharmacol 1995;48:247-51. 24. Day RO, Graham GG, Williams KM, Champion GD, De Jager J. Clinical pharmacology of nonsteroidal antiinflammatory drugs. Pharmacol Ther 1987;33:383-433. 25. Sander O, Hubner G, Turck D, Degner F, Rau R. Meloxicam pharmacokinetics in elderly compared to younger male and female patients with rheumatoid arthritis. Rheumatol Eur 1995;24(suppl. 3):221. 26. Richardson CJ, Blocka KLN, Ross SG, Verbeeck RK. Effects of age and sex on piroxicam disposition. Clin Pharmacol Ther 1985^7:13-8. 27. Turck D, Boulton-Jones M, North N, Heinzel G, Nehmiz G. A phase I study to determine the steady state pharmacokinetics of meloxicam 15 mg capsules in moderate, mild or no renal impairment. Rheumatol Eur 1995;24(suppl. 3):221. 28. Busch U, Heinzel G, Narjes H, Nehmiz G, Krimmer J, Rosch W. Pharmacokinetics of meloxicam in patients with liver insufficiency associated with liver cirrhosis. Rheumatol Eur 1995;24<suppl. 3):177.