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Journal of Clinical Pharmacology, 2004; 44:866-872
© 2004 the American College of Clinical Pharmacology

PEDIATRICS

Pharmacokinetics of Meloxicam in Patients With Juvenile Rheumatoid Arthritis

Rubén Burgos-Vargas, MD, Ivan Foeldvari, MD, Angelika Thon, MD, Ronald Linke, MD and Dietrich Tuerck, PhD

From the Department of Rheumatology, Hospital General de Mexico, Mexico (Dr. Burgos-Vargas); the Pediatric Rheumatology Clinic, Allgemeines Krankenhaus Eilbek, Hamburg, Germany (Dr. Foeldvari); the Department of Pediatric Rheumatology, University Children Hospital, Hannover, Germany (Dr. Thon); and the Department of Clinical Research, Boehringer Ingelheim Pharma KG (Dr. Linke) and the Department of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma KG, Biberach, Germany (Dr. Tuerck).

Address for reprints: Dr. Dietrich Tuerck, Boehringer Ingelheim Pharma KG, Department of Drug Metabolism and Pharmacokinetics, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The pharmacokinetics of a meloxicam suspension were studied in 18 children with juvenile rheumatoid arthritis. Children received a single 0.25-mg/kg dose up to a maximum of 15 mg. Pharmacokinetic parameters after the first dose were calculated by noncompartmental methods. Geometric mean (percent coefficient of variation for geometric mean [gCV]) Cmax, AUC0-{infty}, apparent clearance, apparent volume of distribution, and elimination half-life values were 1.24 µg/mL (47% gCV), 25.6 µg•h/mL (81% gCV), 0.17 mL/min/kg (83% gCV), 0.19 L/kg (63% gCV), and 13.4 hours (54% gCV) in the younger group and 1.89 µg/mL (25% gCV), 35.8 µg•h/mL (21% gCV), 0.12 mL/min/kg (23% gCV), 0.13 L/kg (22% gCV), and 12.7 hours (21% gCV) for the older group, respectively. Area under the curve, volume of distribution, and clearance tended to be higher in the younger group, whereas elimination half-lives were similar. A post hoc comparison to pharmacokinetic data in adults revealed no relevant differences. Thus, a common body weight-normalized dose is considered appropriate for children older than 2 years.

Key Words: Meloxicam • pediatrics • pharmacokinetics • juvenile rheumatoid arthritis (JRA)

Juvenile rheumatoid arthritis (JRA) is the most frequently diagnosed rheumatic disease in children and a major cause of childhood disability, with a reported incidence of 0.07 to 4.01 per 1000 children.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) form the mainstay of treatment, with a satisfactory clinical response seen in 50% to 70% of cases.2 However, the clinical utility of these agents is typically limited by their associated gastrointestinal (GI) toxicity, which may affect up to 50% of treated children.3

This is the first study to address pharmacokinetic aspects of meloxicam in children. Meloxicam is an NSAID of the enolic class that inhibits prostaglandin synthesis via selective inhibition of cyclooxygenase-2 (COX-2) in inflamed joints relative to COX-1 in the GI tract.4 Its pharmacokinetic properties in adults are well characterized and permit convenient once-daily oral dosing.5,6 Meloxicam is approved for the treatment of rheumatic diseases such as osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.

The superior GI tolerability profile of meloxicam suggests that it might be better suited to the treatment of JRA than the commonly used nonselective NSAIDs. Meloxicam is available as an oral suspension formulation that is particularly suitable for use in children because it is easy to administer as well as enabling precise dosage adjustments to be made according to individual body weight. Meloxicam oral suspension has been shown to be bioequivalent to the 15-mg capsule formulation and appears effective and well tolerated for the treatment of osteoarthritis in adults.7

It is of interest to exclude clinically relevant differences between the known pharmacokinetic profiles of meloxicam in adults and children to select a suitable dose or dose range for children of various ages and to avoid underdosing or overdosing on the basis of pharmacokinetics. Therefore, we have assessed the pharmacokinetic properties of meloxicam oral suspension 0.25 mg/kg in 18 children ages 2 to 16 years participating in an open-label study to assess the efficacy and safety of this selective COX-2 inhibitor for the treatment of JRA. This article focuses solely on the results of the pharmacokinetic evaluation. Efficacy and safety data for this study have previously been published.8


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Eligibility criteria have been described previously.8 Male and female patients with oligo- or polyarticular onset-type JRA were eligible for inclusion into this study if they were ages 2 to 16 years and required NSAID therapy. Exclusion criteria included systemic onset-type JRA and other rheumatic conditions, concomitant therapy with other NSAIDs (including topical formulations), concomitant therapy with corticosteroids at doses > 0.3 mg/kg/d, any change in disease-modifying drugs (including corticosteroids) within the previous 3 months, and intra-articular injection of corticosteroids during the 3 months prior to entry into the trial. Patients with concomitant nonrheumatic diseases, abnormal clinically relevant laboratory values nonrelated to JRA (laboratory investigations comprised hematology, biochemistry, and urinalysis, and a pregnancy test was performed to exclude pregnancy), a history of bleeding disorders or active peptic ulcer within the past 6 months, known or suspected hypersensitivity to the trial drug or its excipients, or an incidence of nasal polyps, angioneurotic edema, or urticaria following administration of aspirin or NSAIDs were also excluded.

An attempt was made for this exploratory study to include at least 3 children of each gender into the selected age groups of 2 to 6 and 7 to 16 years. Children were initially recruited at random; latterly, the younger age group was preferentially enrolled to achieve a minimum number in this group.

Study Design
This was a phase I/II, open-label, parallel-group study undertaken at 1 center in Mexico (Hospital General de México) and 2 centers in Germany (Kinderklinik, Universitätsklinikum Hamburg and the Kinderrheumaambulanz, Medizinische Hochschule Hannover). After a washout period of 1 to 3 days, depending on previous therapy (with acetaminophen being allowed as rescue therapy), all patients received a single dose of meloxicam suspension 0.25 mg/kg administered orally, up to a maximum dose of 15 mg for patients weighing ≥ 60 kg. This was followed by a washout period of 72 hours, after which all patients received oral meloxicam suspension 0.25 mg/kg once daily for 52 weeks. All doses were administered with a glass of water (approximately 150-200 mL). Children age < 6 years were required to fast for ≥ 6 hours prior to the first dose of meloxicam, whereas older children fasted for ≥ 12 hours. The first dose of meloxicam was administered 2 hours before a standardized breakfast, with subsequent doses taken after a meal.

The trial was conducted in accordance with the Declaration of Helsinki and its amendments. Each site obtained study approval from its institutional review board and/or relevant ethics committee. In Germany, these were the Landesärztekammer, Baden-Württemberg, Stuttgart; the Ethik-Kommission der Ärztekammer, Hamburg; and the Ethik-Kommission der Medizinischen Hochschule, Hannover. In Mexico, it was the General Hospital of Mexico Ethics Committee. All parents/legal guardians of the patients gave written informed consent.

Pharmacokinetic Analysis
Venous blood samples (2.7 mL) for the determination of plasma drug concentrations were collected by veni-puncture before and 0.5, 1, 2, 3, 5, 8, 12, 24, 48, and 72 hours after administration of the first dose of meloxicam. Further plasma samples for the analysis of steady-state concentrations were taken pre- and postdosing at weeks 2 and 4. Venous blood was collected in EDTA tubes. Plasma was separated by centrifugation at 4000 rpm for 10 min and stored at -20°C until assayed.

Meloxicam plasma concentrations were determined using a specific and validated high-performance liquid chromatography (HPLC) method with a minimum limit of quantification of 0.020 µg/mL. Analytical intra-assay validation revealed an assay precision of 6.8%, with an assay accuracy of ±7.8%.

Pharmacokinetic Variables
Pharmacokinetic variables after single-dose treatment were obtained by established noncompartmental procedures using the TOPFIT® software package (Gustav Fischer, Stuttgart, Germany, Version 2.0). The primary pharmacokinetic parameters evaluated were the maximum drug plasma concentration (Cmax) and the total area under the plasma drug concentration-time curve (AUC0-{infty}). Secondary endpoints included time to achieve peak plasma concentrations (tmax), total area under the plasma drug concentration-time curve from time of administration to the time of the last quantifiable drug concentration (AUC0-t), apparent terminal elimination half-life (t1/2), mean residence time (MRTtot), apparent oral clearance (CL/F), and apparent volume of distribution during the terminal phase (Vz/F). Because the body size of the patients was expected to vary considerably, weight-normalized peak plasma concentrations (NCmax), total area under the plasma drug concentration-time curve (NAUC0-{infty}), clearance (NCL/F), and volume of distribution (NVz/F) were also calculated for an exact dose of 0.25 mg/kg based on the weighted suspension amount given as a single dose and actual body weight to within 1 kg. Steady-state meloxicam plasma concentrations measured at weeks 2 and 4 were compared to the concentrations expected from model predictions using the single-dose data and a 2-compartment model with 3 entry compartments (TOPFIT®, Version 2.0).

Geometric means and percentage coefficients of variation were calculated for all pharmacokinetic variables. All parameters were analyzed according to age group (2-6 years and 7-16 years). Data from children were subsequently compared with those from adults in a previous pharmacokinetic study with oral meloxicam suspension 15 mg.7 This study had enrolled 16 healthy adult male volunteers ages 22 to 45 years.7


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Data are available for 18 children (13 females and 5 males), all of whom completed this pharmacokinetic evaluation. Seven children were ages 2 to 6 years (mean = 3.4 years), and 11 children were ages 7 to 16 years (mean = 10.8 years). Further demographic data are summarized in Table I.


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  		Table I Patient Demographics

 

Key pharmacokinetic findings by age group are shown in Table II, together with comparable adult data.7 Meloxicam plasma concentrations were found to increase rapidly after oral administration, peaking primarily 1 to 3 hours after intake (Figure 1). Most children (16/18) also showed a secondary peak in the concentration-time profile 6 to 12 hours after dosing, with a tertiary peak seen in 2 subjects approximately 24 hours after initial dosing. Cmax values obtained after initial dosing were found to be almost 34% lower in the younger age group than in the older age group (1.20 µg/mL and 1.81 µg/mL, respectively). AUC0-{infty} was also 28% lower in the younger age group than in the older age group (24.8 µg•h/mL and 34.4 µg•h/mL, respectively). NCmax and NAUC0-{infty} demonstrated no relevant difference from the unadjusted values (1.24 µg/mL and 25.6 µg•h/mL, respectively, in younger children compared with 1.89 µg/mL and 35.8 µg•h/mL in the older age group).


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  		Table II Key Pharmacokinetic Parameters by Age Group and Comparable Adult Data

 


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  		Figure 1. Geometric mean meloxicam plasma concentration by age group (2-6 years and 7-16 years) following oral administration of a single dose of 0.25 mg/kg.

 

CL/F tended to be lower in younger children (2.49 mL/min vs. 3.59 mL/min in older children); however, NCL/F tended to be higher (0.17 mL/min/kg in the younger age group vs. 0.12 mL/min/kg in the older age group). As might be expected from their smaller body sizes, Vz/F also appeared to be lower in the younger age group (2.87 L vs. 4.07 L in the older children). Again, however, this pattern was reversed when the values were weight normalized (0.19 L/kg vs. 0.13 L/kg, respectively), and t1/2 and MRTtot were found to be comparable between the younger and older age groups (13.4 h vs. 12.7 h and 20.5 h vs. 19.5 h, respectively). Differences were not tested for statistical significance because the study was powered neither to demonstrate equivalence between the age groups nor to establish an a priori assumed difference.

For all pharmacokinetic variables analyzed, inter-subject variability was much greater among the younger children than in the older age group. This was due to 2 boys (both age 3 years) having drug concentration-time profiles that differed greatly from those of the other subjects in their age group (Figure 2). One of these outliers had a very high Cmax (1.98 µg/mL) coupled with an unexpectedly long elimination half-life of 37.4 hours (NCL/F: 0.05 mL/min/kg), whereas the other attained only very low peak plasma concentrations (0.49 µg/mL), again with a prolonged elimination half-life (16.3 h with NCL/F: 0.48 mL/min/kg). As shown in Table II, omission of data for these 2 subjects greatly reduced the degree of variability in the pharmacokinetic parameters for the younger age group without significantly affecting any of the actual values reported.



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  		Figure 2. Individual and geometric mean meloxicam plasma concentrations for younger children (2-6 years) following oral administration of a single dose of 0.25 mg/kg.

 

Steady-state meloxicam plasma concentrations at weeks 2 and 4 (Table III) were in the range expected from single-dose data. Again, overall variability was high, though expected in this outpatient study, because it was difficult to control for exact timing and conditions of drug intake. To confirm that the measured steady-state concentrations were compatible with the single-dose profile, we fitted a 2-compartment model with 3 entry compartments to mimic the multiple peaks in the drug plasma concentration-time profile to the single-dose data. In general, the single-dose profile could be well fitted, but the model predictions for the steady-state concentrations showed the expected high scatter. Two children showed unexpectedly high predose and postdose drug plasma concentrations at each time point, possibly due to these patients having already taken their daily dose of meloxicam prior to attending the clinic.


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  		Table III Meloxicam Drug Concentrations (µg/mL) in Steady State

 

A post hoc comparison of these findings with historic adult data revealed the pharmacokinetic properties of meloxicam in children to be generally comparable to those seen in adults (Figure 3). Despite a trend toward higher meloxicam concentrations in the older children in this study (Table II), drug plasma concentrations achieved in children are typically within the range seen in adults. Meloxicam elimination half-life was found to be shorter in children (13 h in both ages groups in this study vs. 19 h in adults). A trend toward increased clearance, particularly in young children, was also apparent (NCL/F: 0.17 mL/min/kg for 2- to 6-year-olds compared with 0.12 and 0.11 mL/min/kg in older children and adults, respectively). Mean residence times also appear to be reduced in children (MRTtot: 20.5 and 19.5 h in this study vs. 30.0 h in adults).



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  		Figure 3. Effect of age on meloxicam pharmacokinetics.

 


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This was the first study of a selective COX-2 inhibitor to be undertaken in a pediatric population. The implicit aim of this analysis was to determine whether the pharmacokinetic profile of meloxicam differed in children and adults. We found meloxicam pharmacokinetics in children to be generally comparable to those seen in adults, with the exception of higher rates of clearance and a tendency to increased elimination half-life, particularly in the younger age group. There were no apparent differences between patients of different origin (Mexican or German).

In this study, the drug plasma concentration-time profiles observed regularly showed multiple peaks. This phenomenon is not unexpected for meloxicam, having previously been reported in adults,5 and may be due to pH changes in the GI tract following consumption of food or GI recirculation, as demonstrated previously.9 Meloxicam plasma concentration-time profiles were found to be similar for both age groups studied and, as shown in Figure 3, were generally within the range expected from adult findings (only elderly females show somewhat higher concentrations without relevant consequences for safety). Although a trend toward lower concentrations was apparent among very young children, interindividual variability in all pharmacokinetic properties was found to be much higher in this age group. This appeared to be due to notable deviations in the drug plasma-concentration time profiles in 2 boys in this group, both of whom were only 3 years old. The first boy had very high peak plasma concentrations and a very long elimination half-life (1.98 µg/mL and 37.4 h, respectively). Cytochrome P450 2C9 genotyping was undertaken in this child and was found to be *3/wild type. Because meloxicam predominantly undergoes hepatic metabolism,6 this genotypic combination may account for the low meloxicam clearance seen in this subject, as has previously been reported for other CYP2C9 substrates.10,11 In contrast, the second boy had very low plasma concentrations of meloxicam (0.49 µg/mL), despite appearing to have a longer elimination half-life (16.3 h). However, determination of elimination half-life in this subject was confounded by an unexpectedly low drug concentration in the 48-hour sample. In addition, this child also had a high Vz/F value (9.7 L or 0.69 L/kg vs. a mean value of 0.19 L/kg for this age group). Taken together, these observations suggest that this subject may not have received all of the documented dose of meloxicam on the first day, possibly as a result of spitting out some of the suspension. This is consistent with the observation of higher than expected drug concentrations after multiple doses. As shown in Table II, exclusion of these 2 outliers from the analysis greatly reduced the interindividual variability seen in the younger patients in this study, without influencing the overall trends reported. However, such an omission may be considered to be inappropriate because 11.6% (North Europeans),12 14.4% (white Americans),13 and 23.5% (Spaniards)14 of the Caucasian population were found to have a *3/wild-type genotype, whereas incomplete dosing is likely to be a common problem in very young children.

We also found considerable interindividual variability in steady-state meloxicam plasma concentrations at weeks 2 and 4 taken predose (-1 to 0 h prior to administration) and postdose (3 to 5 h after administration). The large range in values observed was to be expected in this outpatient study because it was difficult to control for exact timing and conditions of drug in-take. Indeed, 2 patients were identified with unexpectedly high predose and postdose drug plasma concentrations at each time point. It seems likely that these patients might have taken their daily dose of meloxicam prior to attending the clinic. Nevertheless, steady-state meloxicam plasma concentrations observed were generally in the range expected from single-dose data and predicted by pharmacokinetic modeling and were consistent with observed steady-state concentrations in adults taking the same formulation.

The increased clearance of meloxicam seen in children compared with adults also merits further attention. Higher rates of clearance in younger children have also been reported for a number of other NSAIDs, including ibuprofen, diclofenac, piroxicam, indomethacin, and tiaprofenic acid, necessitating dose adjustments in some cases.15-20 All of the children included in this pharmacokinetic evaluation were participating in a 52-week open-label study to assess the clinical efficacy and tolerability of an oral meloxicam suspension for the treatment of JRA, results of which have previously been reported.8

Selective COX-2 inhibitors such as meloxicam are increasingly used for the treatment of rheumatic diseases in adults due to their proven efficacy and superior GI tolerability compared with traditional non-selective NSAIDs.21-24 The similarity between the adult and juvenile pharmacokinetic data presented here suggests that the adult dose of 0.25 mg/kg could also be prescribed for children, at least on the basis of unchanged pharmacokinetics, and preliminary safety and efficacy data support this view.8 In concordance, a study of another COX-2 inhibitor, rofecoxib, in JRA patients concluded that a 0.6-mg/kg daily dose in children should approximate the 25-mg once-daily adult dose.25

In conclusion, meloxicam oral suspension 0.25 mg/kg appears to be well suited for once-daily dosing in children, making it a convenient and acceptable alternative to current approaches for the treatment of pediatric rheumatic conditions such as JRA.


   FOOTNOTES
 
DOI: 10.1177/0091270004267589

Submitted for publication March 7, 2003; Revised version accepted May 23, 2004.


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

1. Manners PJ, Bower C: Worldwide prevalence of juvenile arthritis: why does it vary so much? J Rheumatol 2002;29: 1520-1530.[Abstract/Free Full Text]

2. Cassidy JT: Medical management of children with juvenile rheumatoid arthritis. Drugs 1999;58: 831-850.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

3. Dowd JE, Cimaz R, Fink C: Non-steroidal anti-inflammatory drug-induced gastrointestinal injury in children. Arthritis Rheum 1995;38: 1225-1231.[Web of Science][Medline] [Order article via Infotrieve]

4. Engelhardt G, Homma D, Schlegel K, Utzmann R, Schnitzler C: Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 1995;44: 423-433.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Turck D, Roth W, Busch U: A review of the clinical pharmacokinetics of meloxicam. Br J Rheumatol 1996;35(Suppl. 1): 13-16.

6. Davies NM, Skjodt NM: Clinical pharmacokinetics of meloxicam: a cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin Pharmacokinet 1999;36: 115-126.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

7. Hanft G, Türck D, Scheuerer S, Sigmund R: Meloxicam oral suspension: a treatment alternative to solid meloxicam formulations. Inflamm Res 2001;50(Suppl. 1): S35-S37.

8. Foeldvari I, Burgos-Vargas R, Thon A, Tuerck D: High response rate in the phase I/II study of meloxicam in juvenile rheumatoid arthritis. J Rheumatol 2002;29: 1079-1083.[Abstract/Free Full Text]

9. Busch U, Heinzel G, Narjes HH: The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID) in man. Eur J Clin Pharmacol 1995;48: 269-272.[Web of Science][Medline] [Order article via Infotrieve]

10. Miners JO, Birkett DJ: Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998;45: 525-538.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Takahashi H, Kashima T, Nomizo Y, Muramoto N, Shimizu T, Nasu K, et al: Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C and CYP2C19 genotypes. Clin Pharmacol Ther 1998;63: 519-528.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

12. Yasar Ü, Eliasson E, Dahl M-L, Johansson I, Ingelman-Sundberg M, Sjöqvist F: Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999;254: 628-631.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. London SJ, Sullivan-Klose T, Daly AK, Idle JR: Lung cancer risk in relation to the CYP 2C9 genetic polymorphism among Caucasians in Los Angeles County. Pharmacogenetics 1997;7: 401-404.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Garcia-Martin E, Martinez C, Ladero JM, Gamito FJG, Agundez JAG: High frequency of mutations related to impaired CYP2C9 metabolism in a Caucasian population. Eur J Clin Pharmacol 2001;57: 47-49.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Olkkola KT, Naunuksela E-L, Korpela R: Pharmacokinetics of postoperative intravenous indomethacin in children. Pharmacol Toxicol 1989;65: 157-160.[Web of Science][Medline] [Order article via Infotrieve]

16. Korpela R, Olkkola KT: Pharmacokinetics of intravenous diclofenac sodium in children. Eur J Clin Pharmacol 1990;38: 293-295.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

17. Bertin L, Rey E, Pons G, Mathist JL, Richard MO, Chretien P, et al: Pharmacokinetics of tiaprofenic acid in children after a single oral dose. Eur J Clin Pharmacol 1991;41: 251-253.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

18. Mäkelä A-L, Olkkola KT, Mattila MJ: Steady state pharmacokinetics of piroxicam in children with rheumatoid diseases. Eur J Clin Pharmacol 1991;41: 79-81.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

19. Nahata MC, Durrell DE, Powell DA, Gupta N: Pharmacokinetics of ibuprofen in febrile children. Eur J Clin Pharmacol 1991;40: 427-428.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

20. Rey A, Pariente-Khayat A, Gouyet L, Vauzelle-Kervroedan F, Pons G, D'Athis P, et al: Stereoselective disposition of ibuprofen enantiomers in infants. Br J Clin Pharmacol 1994;38: 373-375.[Web of Science][Medline] [Order article via Infotrieve]

21. Dequeker J, Hawkey C, Kahan A, Steinbrück K, Alegre C, Baumelou E, et al: Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX-inhibiting Therapies (SELECT) trial in osteoarthritis. Br J Rheumatol 1998;37: 946-951.[Abstract/Free Full Text]

22. Hawkey C, Kahan A, Steinbrück K, Alegre C, Baumelou E, Begaud B, et al: Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients. Br J Rheumatol 1998;37: 937-945.[Abstract/Free Full Text]

23. Hawkey CJ, Jackson L, Harper SE, Simon TJ, Mortesen E, Lines CR, et al: The gastrointestinal safety profile of rofecoxib, a highly selective inhibitor of cyclooxygenase-2, in humans. Aliment Pharmacol Ther 2001;15: 1-9.[Web of Science][Medline] [Order article via Infotrieve]

24. Deeks JJ, Smith LA, Bradley MD: Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Br Med J 2002;325: 619-626.[Abstract/Free Full Text]

25. St. Rose E, Ferrandiz M, Kiss M, Forre O, Vehe R, Higgins G, et al: Steady-state plasma concentrations of rofecoxib in children (ages 2-5 years) with juvenile rheumatoid arthritis (JRA) [abstract OP0094]. EULAR 2001.
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