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Clinical Pharmacokinetics and Pharmacodynamics of Celecoxib a Selective Cyclo-Oxygenase-2 Inhibitor

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Clinical Pharmacokinetics and Pharmacodynamics of Celecoxib a Selective Cyclo-Oxygenase-2 Inhibitor Clin Pharmacokinet 2000 Mar; 38 (3): 225-242 DRUG DISPOSITION 0312-5963/00/0003-0225/$20.00/0 © Adis International Limited. All rights reserved. Clinical Pharmacokinetics and Pharmacodynamics of Celecoxib A Selective Cyclo-Oxygenase-2 Inhibitor Neal M. Davies,1 Andrew J. McLachlan,1 Ric O. Day2 and Kenneth M. Williams2 1 Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia 2 Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, University of New South Wales, Sydney, New South Wales, Australia Contents Abstract . 225 1. Analytical Methods . 227 2. Pharmacokinetic Properties . 227 2.1 Absorption . 227 2.2 Distribution . 231 2.2.1 Distribution and Protein Binding . 231 2.2.2 Distribution into Synovial Fluid/Synovium . 231 2.3 Metabolism and Elimination . 232 3. Implications of Pharmacokinetic and Pharmacodynamic Properties for Therapeutic Use . 232 3.1 Racial and Genetic Polymorphism . 232 3.2 Specific Inhibition of Cyclo-Oxygenase-2 (COX-2) . 232 3.3 Potential of Selective Inhibitors of COX-2 in Prevention of Myocardial Infarction, Stroke and Angina . 233 3.4 Dosage and Therapeutic Range . 234 3.5 Effectiveness and Safety . 235 3.6 Disease and Celecoxib . 236 3.6.1 Renal Insufficiency . 236 3.6.2 Hepatic Insufficiency . 236 3.6.3 Rheumatic Disorders . 237 3.6.4 Endotoxinaemia . 237 3.6.5 Colorectal Cancer . 237 3.6.6 Alzheimer’s Disease . 237 3.7 Influence of Age and Gender on Celecoxib Pharmacokinetics . 238 3.8 Pregnancy and Lactation . 238 4. Pharmacokinetic Drug Interactions . 239 4.1 Effect of Other Drugs on the Pharmacokinetics of Celecoxib . 239 4.2 Effect of Celecoxib on the Pharmacokinetics of Other Drugs . 239 5. Conclusions . 240 Abstract Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first spe- cific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib also has 226 Davies et al. analgesic and anticancer properties. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac). The rate of absorption of celexocib is moderate when given orally (peak plasma drug concentration occurs after 2 to 4 hours), although the extent of absorption is not known. Celexocib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455 ± 166L in humans. The area under the plasma concentration-time curve (AUC) of celecoxib increases in proportion to increasing oral doses between 100 and 800mg. Celecoxib is eliminated following biotransformation to carboxylic acid and glu- curonide metabolites that are excreted in urine and faeces, with little drug (2%) being eliminated unchanged in the urine. Celecoxib is metabolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about 11 hours in healthy individuals. Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib. Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been re- ported that the steady-state AUC is increased by approximately 40% and 180% in patients with mild and moderate hepatic impairment, respectively. Celecoxib does not appear to interact with warfarin, ketoconazole or metho- trexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, in- creased clinical vigilance is required during the coadministration of other sub- strates or inhibitors of this enzyme. Celecoxib, 4-[5-(4-methylphenyl)-3-trifluoro- cules effective in selectively inhibiting COX-2 methyl-1H-pyrazoyl-1-yl]benzene sulphonamide, is with little or no effect on COX-1. The major clini- a 1,5-diaryl-substituted pyrazole with a pKa of 11.1 cal goal was to produce an NSAID that had little or (fig. 1). Celecoxib (Celebrex®; Searle-Monsanto no effects on the gastrointestinal (GI) tract and and Pfizer) was the first specific inhibitor of cyclo- kidney. oxygenase-2 (COX-2) to be approved by the US In vitro assays demonstrate that celecoxib is a Food and Drug Administration (FDA), on Decem- potent inhibitor of prostaglandin synthesis.[4] In ber 31, 1998. In the treatment of patients with rheu- vitro assays of inhibition of recombinant human matoid arthritis, osteoarthritis, and for management COX-1 and -2 demonstrated that the concentra- of the pain of these conditions, therapeutic doses tions of celecoxib required to achieve 50% inhibi- of celecoxib have proven to be equi-efficacious tion of the enzyme (IC50)are15± 1 μg/L for COX- when compared with other commonly used nonste- 1 and 0.04 ± 0.01 μg/L for COX-2.[5] In cells roidal anti-inflammatory drugs (NSAIDs), including expressing COX-1 or -2, the IC50 values for the diclofenac, naproxen and ibuprofen.[1-3] The clinical COX-1 and -2 isozymes were 13 to 15 and 0.05 introduction of celecoxib in 1999 has been the cul- μg/L, respectively.[6,7] This suggests that celecoxib mination of the important discovery of the COX possesses a selectivity ratio for COX-1 : COX-2 isoenzymes and the subsequent search for mole- activity of >375. © Adis International Limited. All rights reserved. Clin Pharmacokinet 2000 Mar; 38 (3) Celecoxib 227 NH2 O the first commercially available specific COX-2 S inhibitor are reviewed. O N N 1. Analytical Methods CF3 To date there is only one published report de- scribing a method for analysis of celecoxib. Plasma concentrations of celecoxib were determined by CH 3 high performance liquid chromatography (HPLC) Fig. 1. Structure of celecoxib. with a quantitation limit of 10 μg/L. This method involved the use of a C18 column and employed GI complications are the most common adverse ultraviolet detection.[14] There is no information effect of the NSAIDs. However, as celecoxib does available on analysis of metabolite concentrations. not inhibit the enzyme COX-1 at concentrations achieved in vivo after usual clinical doses, there are 2. Pharmacokinetic Properties putative GI safety advantages compared with other NSAIDs. As celecoxib is structurally a benzene 2.1 Absorption sulphonamide (fig. 1), it should be administered with caution to patients who have demonstrated Celecoxib is administered orally in conventional allergic-type reactions to sulphonamides. A recent release capsules, with doses of 100mg and 200mg meta-analysis suggests that the potential for cross- commercially available. After a single oral 200mg allergenicity between celecoxib and the sulfanam- dose to healthy young volunteers the mean maxi- ide-containing medications appears comparable mum drug plasma concentrations (Cmax) of celecoxib [9] with that of placebo and other nonsulfonamide were reached after between 2 and 4 hours (table I). After an oral dose of 300mg, administered as a containing NSAIDs.[8] Prospective trials are needed fine aqueous suspension of the 14C-labelled drug to confirm these findings. Additionally, celecoxib or as a capsule, Cmax occurred 1.9 hours after ad- should not be prescribed for patients who have [15] ministration. Both the Cmax and area under the asthma, urticaria or allergic-type reactions after concentration-time curve (AUC) were linearly re- [9] taking aspirin (acetylsalicylic acid) or NSAIDs. lated to dose within the clinical range of 100 to [10-13] There are a number of general review articles 600mg.[14] Because of the lack of an intravenous available that deal with the pharmacological prop- form of celecoxib, apparently because of poor sol- erties and therapeutic indications of selective COX-2 ubility, absolute bioavailability studies have not inhibition; however, these articles do not discuss, been conducted. Table II provides a summary of in detail, the clinical pharmacokinetics and phar- the absorption parameters [Cmax, time to peak con- macodynamics of celecoxib. In this article, the clin- centration (tmax) and AUC] for celecoxib in both ical pharmacokinetics and pharmacodynamics of healthy individuals and patients. Table I. Concentrations of celecoxib and metabolites (M1, M2 and SC-60613) in plasma. Values are percentages of total radioactivity in plasma samples[9] Time post-dose (h) n Metabolite 1 Metabolite 2 SC-60613 Celecoxib 0.5 8 1.10 ± 0.60 12.1 ± 2.6 2.43 ± 0.89 84.4 ± 3.6 3 8 21.0 ± 4.9 21.2 ± 1.9 0.217 ± 0.182 57.6 ± 6.5 4 2 13.5 21.0 ND 65.6 12 6 23.2 ± 4.1 27.0 ± 5.9 ND 49.9 ± 4.5 n = number of patients; ND = not detectable. © Adis International Limited. All rights reserved. Clin Pharmacokinet 2000 Mar; 38 (3) 228 Davies et al. Table II. Absorption characteristics of celecoxib. Values relate to oral formulations administered as single doses to healthy adults, except where indicated, and are means ± SD where available a Dose (mg) n Age (y) Cmax (μg/L) tmax (h) AUC (μg/L • h) Reference 300 (14C 100μCi) NR NR 1527.0 ± 638.0 NR NR 16 300 (14C 100μCi) NR NR 1077.0 ± 649.0 2.0 8764.0 5 4 (total study 80) NR 28.0 ± 9.7 1.6 ± 1.1 4.5 ± 0.8 9 25 4 (total study 80) 133.3 ± 45.2 1.3 ± 0.5 10.3 ± 3.8 50 4 (total study 80) 233.3 ± 45.1 2.0 ± 1.2 7.7 ± 2.7 100 4 (total study 80) 362.0 ± 156.0
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