Abstract
Objective
The effect of multiple oral doses of meloxicam 15 mg on the pharmacodynamics and pharmacokinetics of warfarin was investigated in healthy male volunteers. Warfarin was administered in an individualized dose to achieve a stable reduction in prothrombin times calculated as International Normalized Ratio (INR) values. Then INR- and a drug concentration-time profile was determined. For the interaction phase, meloxicam was added for 7 days and then INR measurements and the warfarin drug profiles were repeated for comparison. Overall, warfarin treatment lasted for 30 days.
Results
Warfarin and meloxicam were well tolerated by healthy volunteers in this study. Thirteen healthy volunteers with stable INR values entered the interaction phase. Prothrombin times, expressed as mean INR values, were not significantly altered by concomitant meloxicam treatment, being 1.20 for warfarin alone and 1.27 for warfarin with meloxicam cotreatment. R- and S-warfarin pharmacokinetics were similar for both treatments. Geometric mean (% gCV) AUCSs values for the more potent S-enantiomer were 5.07 mg·h·l-1 (27.5%) for warfarin alone and 5.64 mg·h·l-1 (28.1%) during the interaction phase. Respective AUCss values for R-warfarin were 7.31 mg·h·l-1 (43.8%) and 7.58 mg·h·r-1 (39.1%).
Conclusion
The concomitant administration of the new non-steroidal anti-inflammatory drug (NSAID) meloxicam affected neither the pharmacodynamics nor the pharmacokinetics of a titrated warfarin dose. A combination of both drugs should nevertheless be avoided and, if necessary, INR monitoring is considered mandatory.
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References
Engelhardt G, Homma D, Schlegel K, Schnitzler Chr, Utzmann R (1995) Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new nonsteroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 44: 423–33
Engelhardt G, Bögel R, Schnitzer Chr, Utzmann R (1996) Meloxicam: Influence on arachidonic acid metabolism. Part I: In vitro findings. Biochem Pharmacol 51: 21–28
Churchill L, Graham AG, Shih C-K, Pauletti D, Farina PR, Grob PM (1996) Selective inhibition of human cyclooxygenase-2 by meloxicam. Inflammopharmacol 4: 125–135
Pairet M, Engelhardt G (1996) Differential inhibition of COX-1 and C0X-2 in vitro and pharmacological profile in-vivo of NSAIDs. In: Vane J, Botting J, Botting R (eds) Improved nonsteroid anti-inflammatory drugs — COX-2 enzyme inhibitors. Kluwer Academic Publishers, Dordrecht, pp 103–119
Distel M, Mueller C, Bluhmki E (1996) Global analysis of gastrointestinal safety of a new NSAID, meloxicam. Inflammopharmacol 4: 71–81
Anonymous (1988) Management of venous thromboembolism. Lancet 1: 275–277
Mirsen TR, Hachisnki VC (1988) Transient ischaemic attacks and stroke. Can Med Ass J 138: 1099–1105
Stein B, FusterV (1989) Antithrombotic therapy in acute myocardial infarction: prevention of venous, left ventricular and coronary artery thromboembolism. Am J Cardiol 64: 33B-40B
HirshJ (1991) Oral anticoagulant drugs. N Engl J Med 324: 1865–1875
Lewis RJ, Träger WF, Chan KK, Breckenridge A, OrmeM, Roland M, ScharyW (1974) Warfarin: stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 53: 1607–1617
O’Reilly RA, Trager WF, Motley EH, Howald W (1980) Stereoselective interaction of phenylbutazone with 13C/12C-pseudoracemates of warfarin in man. J Clin Invest 65: 746–753
Schulman S, Henriksson K (1989) Interaction of ibuprofen and warfarin on primary haemostasis. Br J Rheumatol 28: 46–49
Stricker BH, Delhes JL (1982) Interaction between flurbiprofen and coumarins. BMJ 285: 1139
Serlin MJ, Breckenridge AM (1983) Drug interactions with warfarin. Drugs 25: 610–620
Verbeeck RK, Blackburn JL, Loewen GR (1983) Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs. Clin Pharmacokin 8: 297–331
Yacobi A, Levy G (1977) Protein binding of warfarin enantiomers in serum of humans and rats. J Pharmacokin Biopharm 5: 123–131
Verbeeck RK (1990) Pharmacokinetic drug interactions with nonsteroidal inflammatory drugs. Clin Pharmacokin 19: 44–66
Rolan PE (1994) Plasma protein binding displacement interactions — why are they still regarded as clinically important? Br J Clin Pharmacol 37: 125–128
O’Reilly RA, Trager WF, Motley CH, Howard W (1980) Interaction of secobarbital with warfarin pseudoracemates. Clin Pharmacol Ther 28: 187–195
Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, Gelboin HV, Gonzalez FJ, Trager WF (1992) Hydroxylation of warfarin by human c-DNA expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin drug interactions. Chem Res Toxicol 5: 54–59
Newlands AJ, Smith DA, Jones BC, Hawsworth GM (1992) Metabolism of nonsteroidal anti-inflammatory drugs by cytochrome P4502C. Br J Clin Pharmacol 34: 152P
KondoM, Zhao J, Leeman T, Dayer P (1992) Biotransformation of oxicam NSAIDs by human cytochrome P450TB (CYP2C). Abstracts of the Vth world Conference on clinical pharmacology and therapeutics. Yokohama, Japan 243
Guengerich FP (1990) Mechanisms based inactivation of human liver microsomal cytochrome p-450 II A4 by gestodene. Chem Res Toxicol 3: 363–371
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome p-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270: 414–423
Roden DM, Woosley RL (1983) Class I antiarrhythmic agents: quinidine, procainamide and N-acetylprocainamide, disopyramide. Pharmacol Ther 23: 179–191
Andersen C, Balmer K, Lagerström PO (1993) Enantioselective assay of warfarin in blood plasma by liquid chromatography on Chiralcel OC. J Chromatogr 615: 159–163
Heinzel G, Woloszczak, Thomann R (1993) TopFit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the PC. Gustav Fischer, Stuttgart
Steinijans VW, Hartmann M, Huber R, Radtke HW (1991) Lack of pharmacokinetic interaction as an equivalence problem. Int J Clin Pharmacol Ther Toxicol 29: 323–328
Chan E, McLachlan AJ, Pegg M, MacKay AD, Cole RB, Rowland M (1994) Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin. Br J Clin Pharmacol 37: 563–569
Türck D, Busch U, Heinzel G, Narjes H (1996) Clinical pharmacokinetics of meloxicam. Br J Rheumatol 15 Suppl 1: 23–30
Eichler HG, Jung M, Kyrle PA, Rotter M, Korn A (1992) Absence of interaction between tenoxicam and warfarin. Eur J Clin Pharmacol 42: 227–229
Ravic M, Johnston A, Turner P (1990) Clinical pharmacological studies of some possible interactions of lornoxicam with other drugs. Postgrad Med J 66 Suppl 4: S30-S34
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Türck, D., Su, C.A.P.F., Heinzel, G. et al. Lack of interaction between meloxicam and warfarin in healthy volunteers. Eur J Clin Pharmacol 51, 421–425 (1997). https://doi.org/10.1007/s002280050224
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DOI: https://doi.org/10.1007/s002280050224