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

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 specific 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 reported 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 methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates 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.

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.

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 1.4 ± 0.75 8.5 ± 2.9 200 4 (total study 80) 797.0 ± 498.8 1.8 ± 1.50 7.6 ± 5.5 200 + high fat breakfast 4 (total study 80) 876.5 ± 749.5 6.3 ± 4.03 9.5 ± 5.6 400 4 (total study 80) 706.8 ± 104.1 2.3 ± 1.5 7.6 ± 5.5 400 + high fat breakfast 2 (total study 80) 1355.0 ± 7.1 6.0 ± 2.8 4.2 ± 2.3 600 4 (total study 80) 1771.0 ± 625.1 1.5 ± 1.0 9.6 ± 3.7 900 20 (total study 80) 1419.3 ± 683.4 1.9 ± 0.9 10.9 ± 5.2 1200 4 (total study 80) 2022.5 ± 752.0 2.0 ± 0.8 16.4 ± 17.3 40 8 (17-44) 197.0 ± 86.0 1.5 ± 0.5 1217.0 ± 328.0 9 200 7 646.0 ± 341.0 1.6 ± 0.7 5986.0 ± 4032.0 400 8 1433.0 ± 523.0 2.1 ± 0.8 13341.0 ± 3010.0 40 single dose followed 48h later by bid 8 183.0 ± 52.0 1.94 ± 0.9 937.0 ± 288.0 × 7 days 200 single dose followed 48h later by bid 8 1115.0 ± 425.0 1.8 ± 0.7 6726.0 ± 3858.0 × 7 days 400 single dose followed 48h later by bid 8 1833.0 ± 478.0 1.6 ± 1.0 11634.0 ± 3745.00 × 7 days 40 36 (40-58) 277.0 ± 77.0 3.4 ± 3.5 1928.0 ± 568.0 9 200 759.0 ± 374.0 2.5 ± 1.7 9941.0 ± 4488.0 400 1103.0 ± 309.0 1.9 ± 0.7 14064.0 ± 5428.00 40 single dose followed 48h later by bid × 326.0 ± 119.0 1.7 ± 0.6 1687.0 ± 601.0 17 days 200 single dose followed 48h later by bid 1187.0 ± 393.0 2.1 ± 1.0 8155.0 ± 2427.0 × 17 days 400 single dose followed 48h later by bid 1805.0 ± 642.0 3.8 ± 3.6 13355.0 ± 6599.0 × 17 days 200 (commercial capsule) 36 NR 705.00 ± 38.00 2.8 ± 37.0 7830.0 9 200 (suspension) 36 NR 1229.00 0.8 8001.0 200 (2 × 100 Phase II capsule) 36 NR 620.00 3.0 7562.0 200 fasting 24 NR 806.0 ± 411 2.4 ± 0.8 5884.0 ± 2293.0 9 200 high fat meal 1042.0 ± 355 3.4 ± 1.3 7141.0 ± 2787.0 200 medium fat meal 952 ± 244 3.7 ± 0.8 6607.0 ± 2719.0 200 + antacid 507 ± 259 2.5 ± 1.1 5729.0 ± 2628.0 50 fasting 24 NR 321.0 ± 178.0 2.9 ± 1.6 2694.0 ± 2592.0 9 50 fed 354.0 ± 130.0 4.5 ± 1.4 2759.0 ± 2281.0 100 fasting 455.0 ± 275.0 2.6 ± 1.2 5127.0 ± 4020.0 100 fed 747.0 ± 382.0 5.0 ± 2.4 5419.0 ± 3890.0 200 NR NR 1052.0 ± 324.0 4.0 ± 1.2 NR 9 200 bid × 7 days 1255.0 ± 406.0 3.8 ± 0.5 NR 400 daily 1760.0 ± 634.0 4.6 ± 1.2 NR 400 single dose AM NR NR 2893.0 ± 930.0 3.1 ± 1.2 22160.0 ± 7463.0 9 400 single dose followed 3 days later by 2565.0 ± 738.0 3.2 ± 0.6 18955.0 ± 6001.0 400 at 08.00h with low fat meal × 10 days 400 single dose followed 3 days later by 2214.0 ± 758.0 4.5 ± 1.9 21034.0 ± 7703.0 400 at 19.00h with low fat meal × 10 days

Table II. Contd a Dose (mg) n Age (y) Cmax (μg/L) tmax (h) AUC (μg/L • h) Reference 200 day 1, followed by 200 bid begun on 24 <50 598.3 3.4 6694.0 9 day 3 and ending after a single morning 973.2 2.7 9697.0 dose on day 10 200 day 1, followed by 200 bid begun on 24 >65 1019.0 1.9 10143.0 day 3 and ending after a single morning 1808.0 2.4 19446.0 dose on day 10 200 12 male >65 1254.0 NR 8238.0 9 200 11 male <50 1089.0 NR 6440.0 200 12 female >65 2362.0 NR 15466.0 200 13 female <50 875.3 NR 5389.0 200 bid × 5 days 24 (GFR 60-130 (65-85) 1588.0 3.3 10313.0 9 2 400 bid × 5 days ml/min/1.73 m ) 2824.0 3.8 20027.0 200 bid × 7 days - day 1 22 (GFR 34-48 (43-78) 509.0 4.5 2457.0 9 2 200 bid × 7 days - day 7 ml/min/1.73 m ) 662.0 4.3 5003.0 100 day 1 followed by 100 bid × 8 days - 12 mild HI (43-78) 526.0 2.2 3791.0 9 day 1 100 day 1 followed by 100 bid × 8 days - 629.0 1.9 3518.0 day 8 100 day 1 followed by 100 bid × 8 days - 12 healthy control 342.2 2.17 2999.0 day 1 100 day 1 followed by 100 bid × 8 days - 421.8 2.08 2575.0 day 8 100 day 1 followed by 100 bid × 8 days - 12 moderate HI (43-78) 459.0 2.8 6554.0 9 day 1 100 day 1 followed by 100 bid × 8 days - 952.0 2.0 6458.0 day 8 100 day 1 followed by 100 bid × 8 days - 12 healthy control 326.0 2.9 2663.0 day 1 100 day 1 followed by 100 bid × 8 days - 425.0 1.9 2288.0 day 8 200 bid 24 NR 850.7 ± 296.0 2.8 ± 1.0 8696.0 ± 3611.0 9 200 bid + lithium CR 450 bid 996.1 ± 385.8 2.4 ± 0.8 8932.0 ± 4113.0 200 bid + glibenclamide 5 daily or 10 bid 10 NIDDM NR 1211.0 ± 373.3 2.5 ± 0.8 8177.7 ± 3965.1 9 200 bid + glibenclamide 10 bid 14 NIDDM 1435.9 ± 767.0 2.5 ± 0.8 9748.1 ± 6289.2 200, day 1 17 NR 753.3 ± 289.0 2.9 ± 1.3 8133.5 ± 2679.2 17 200/day, day 9 17 NR 649.0 ± 322.0 2.6 ± 0.82.8 7397.3 ± 2819.7 200, day 1 + KNZ 200/day × 7 days 17 NR 4567.4 ± 320.3 3.5 ± 1.9 7850.5 ± 2294.0 200, day 1 + FNZ 200/day × 7 days 17 NR 1038.7 ± 377.3 3.4 ± 1.6 17103.8 ± 5424.0 100 37 (21-49) 550.0 ± 65.0 4.1 ± 0.6 4514.0 ± 531.0 14 400 971.0 ± 115.0 4.3 ± 0.9 11282.0 ± 1339.0 800 2 929.0 ± 437.0 4.0 ± 0.1 23109.0 ± 6318.0 a Mean age; range in parentheses.

AUC = area under the concentration-time curve; bid = twice daily; Cmax = peak plasma drug concentration; CR = controlled release; FNZ = fluconazole; GFR = glomerular filtration rate; HI = hepatic impairment; KNZ = ketoconazole; NIDDM = type 2 (non–insulin-dependent) diabetes mellitus; NR = not reported; tmax = time taken to achieve Cmax.

In single dose studies, coadministration of a conditions.[9] Coadministration of celecoxib with high fat (75g) meal led to a delay in the Cmax of aluminium- or magnesium-containing antacids re- between 1 and 2 hours and the AUC was increased sulted in a 37% decrease in the Cmax and a 10% significantly, by 10 to 20%, compared with fasting decrease in AUC.[9]

Table III. Pharmacokinetic properties of celecoxib in healthy volunteers. Values are for oral immediate release dosage forms administered as single doses, except where indicated, and are means ± SD where available a Dose (mg) n Age (y) t1⁄2β (h) V/F (L/kg) CL/F (L/h) Reference 300 (14C 100μCi) NR NR 15.6 NR NR 16 300 (14C 100μCi) NR NR NR NR NR 5 4 (total study 80) NR 4.5 ± 0.8 NR NR 9 25 4 (total study 80) 10.3 ± 3.8 NR NR 50 4 (total study 80) 7.7 ± 2.7 NR NR 100 4 (total study 80) 8.5 ± 2.9 NR NR 200 4 (total study 80) 7.6 ± 5.6 NR NR 200 + high fat breakfast 4 (total study 80) 9.5 ± 5.6 NR NR 400 4 (total study 80) 7.5 ± 2.4 NR NR 400 + high fat breakfast 2 (total study 80) 4.2 ± 2.3 NR NR 600 4 (total study 80) 9.6 ± 3.7 NR NR 900 20 (total study 80) 10.9 ± 5.2 NR NR 1200 4 (total study 80) 16.4 ± 17.3 NR NR 40 8 (17-44) 4.2 ± 2.0 194.0 ± 81.5 34.3 ± 9.6 9 200 7 8.0 ± 2.3 483.0 ± 260.0 40.1 ± 14.4 400 8 8.9 ± 3.6 408.0 ± 208.0 31.4 ± 6.9 40 single dose followed 48h later by bid × 7 days 8 3.9 ± 1.6 239.0 ± 98.0 45.1 ± 14.4 200 single dose followed 48h later by bid × 7 days 8 7.1 ± 2.33 346.0 ± 176.0 33.9 ± 10.8 400 single dose followed 48h later by bid × 7 days 8 9.6 ± 4.2 557.0 ± 407.0 38.2 ± 13.8 40 36 (40-58) 7.7 ± 2.9 244.0 ± 107.0 22.6 ± 7.5 9 200 15.2 ± 7.6 467.0 ± 196.0 25.1 ± 15.2 400 14.5 ± 5.7 649.0 ± 269.0 32.7 ± 13.6 40 single dose followed 48h later by bid × 17 days 7.4 ± 1.7 270.0 ± 78.0 26.2 ± 8.4 200 single dose followed 48h later by bid × 17 days 12.1 ± 3.7 465.0 ± 205.0 26.2 ± 6.6 400 single dose followed 48h later by bid × 17 days 14.2 ± 4.5 796.0 ± 517.0 36.4 ± 15.7 200 (commercial capsule) 36 NR 11.9 NR 27.7 9 200 (suspension) 36 NR 13.3 NR 27.1 200 (2 × 100 Phase II capsule) 36 NR 14.0 NR 29.0 200 fasting 24 NR 14.1 ± 11.4 NR NR 9 200 high fat meal 6.3 ± 2.8 NR NR 200 medium fat meal 6.2 ± 2.5 NR NR 200 antacid 10.6 ± 3.1 NR NR 50 fasting 24 NR 11.0 ± 6.7 NR NR 9 50 fed 6.5 ± 3.9 NR NR 100 fasting 16.0 ± 10.2 NR NR 100 fed 6.9 ± 3.0 NR NR 400 single dose AM NR NR 7.7 ± 2.4 NR NR 9 400 single dose followed 3 days later by 400 at 10.1 ± 8.7 NR NR 08.00h with low fat meal × 10 days 400 single dose followed 3 days later by 400 at 7.3 ± 2.8 NR NR 19.00h with low fat meal × 10 days 200 day 1, followed by 200 bid begun on day 3 24 <50 11.7 533.0 31.7 9 and ending after a single morning dose on day 10 11.3 630.0 38.4 200 day 1, followed by 200 bid begun on day 3 24 >65 12.8 390.0 22.3 and ending after a single morning dose on day 10 12.4 448.0 23.7 200 12 male >65 NR NR 26.0 9 200 11 male <50 NR NR 35.1 200 12 female >65 NR NR 22.3 200 13 female <50 NR NR 42.0

Table III. Contd a Dose (mg) n Age (y) t1⁄2β (h) V/F (L/kg) CL/F (L/h) Reference 200 bid × 5 days 24 (GFR 60-130 (65-85) NR NR 21.3 9 2 400 bid × 5 days ml/min/1.73 m ) NR NR 21.7 200 bid × 7 days - day 1 22 (GFR 34-48 NR NR NR 9 2 200 bid × 7 days - day 7 ml/min/1.73 m ) NR NR 41.5 100 day 1 followed by 100 bid × 8 days - day 1 12 mild HI (43-78) 11.2 NR 34.5 9 100 day 1 followed by 100 bid × 8 days - day 8 11.0 NR 32.9 100 day 1 followed by 100 bid × 8 days - day 1 12 healthy controls 10.8 NR 37.1 100 day 1 followed by 100 bid × 8 days - day 8 10.4 NR 38.0 100 day 1 followed by 100 bid × 8 days - day 1 12 moderate HI (43-78) 14.0 NR 18.8 9 100 day 1 followed by 100 bid × 8 days - day 8 13.6 NR 16.2 100 day 1 followed by 100 bid × 8 days - day 1 12 healthy controls 11.0 NR 40.5 100 day 1 followed by 100 bid × 8 days - day 8 10.7 NR 43.4 200 day 1 17 NR 9.6 NR NR 17 200/day - day 9 17 NR 11.0 NR NR 200 day 1 + KNZ 200/day × 7 days 17 NR 11.2 NR NR 200 day 1 + FNZ 200/day × 7 days 17 NR 11.2 NR NR a Mean age; range in parentheses. bid = twice daily; CL/F = apparent clearance of drug from plasma after oral administration; FNZ = fluconazole; GFR = glomerular filtration rate; HI = hepatic impairment; KNZ = ketoconazole; n = number of participants; NR = not reported; t1⁄2β = elimination half-life; V/F = apparent volume of distribution after oral administration.

2.2 Distribution substrate, arachidonic acid. The supply of arachidonic acid to COX-2 may determine the effective- 2.2.1 Distribution and Protein Binding ness of NSAIDs, as supplying arachidonic acid Most traditional NSAIDs are highly (>98%) leads to increased prostanoid production and sub- protein bound to albumin and have an apparent sequently reduces the effectiveness of NSAIDs, in- volume of distribution (V/F) ranging from 0.1 to cluding selective COX-2 inhibitors.[19] NSAIDs 0.3 L/kg. This volume of distribution is much lower may inhibit prostanoid production in a manner that than the volume of total body water (0.6 L/kg) and is is inversely related to arachidonic acid supply. It [15] equivalent to plasma or blood volume. Cele- has been suggested that COX-2 inhibitors are less coxib is also extensively (>97%) protein bound, effective at more inflamed sites where phospho- primarily to albumin. The fraction of unbound drug [19] lipaseA2 activity is increased. This may provide remains essentially constant (mean 2.6% unbound) a rational explanation for the observation that at total plasma celecoxib concentrations up to 4000 higher dosages of celecoxib are required for the μ [9] 14 g/L. Based on measurement of total C radio- management of patients with rheumatoid arthritis activity, celecoxib is evenly distributed between as compared with patients with osteoarthritis.[20] erythrocytes and plasma (red blood cell/plasma = The distribution of specific COX-2 inhibitors 0.89).[18] Celecoxib has an V/F of 455 ± 166L in into the synovium may be an extremely important humans (5.7 to 7.1 L/kg) [table II].[9,18] This larger determinant of the effectiveness of this class of than expected V/F when compared with other compounds. However, there are no published data NSAIDs may relate to the lipophilic nature of on either synovial fluid or synovium concentrations celecoxib or be reflective of a low bioavailability. of celecoxib. Based on the relatively high protein 1 2.2.2 Distribution into Synovial Fluid/Synovium binding and intermediate elimination half-life (t ⁄2β), Recent preclinical studies suggest that in- one might expect the relative distribution between creased prostanoid production in inflammation re- blood and synovial fluid to be similar to the syno- quires increased COX-2 expression and increased vial fluid concentrations displayed by naproxen.[20]

The impact of the lipophilic properties of celecoxib 3. Implications of Pharmacokinetic on trans-synovial transport is unclear. and Pharmacodynamic Properties NSAIDs account for a high percentage of reported for Therapeutic Use serious adverse drug reactions.[21] As a consequence, there has been considerable interest in the develop- 3.1 Racial and Genetic Polymorphism ment of topical NSAIDs in recent years with the A meta-analysis of pharmacokinetic studies has aim of providing local action without systemic ad- suggested an approximately 40% higher AUC and verse effects. When applied topically, these drugs 11% lower CL/F of celecoxib in Blacks compared are formulated to penetrate the skin barrier in suf- with Caucasians.[9] The reason for these pharmaco- ficient amounts to reach the subadjacent joints and kinetic differences is unclear. muscles and exert therapeutic activity. Local en- Variants at several amino acid residues lead to hanced topical delivery may also allow the clini- genetic polymorphism in the coding region of the cian to deliver a specific COX-2 inhibitor to the site CYP2C9 gene.[23] Markedly diminished metabolic of action and increase the therapeutic ratio even capacity for CYP2C9 substrates and wide variabil- further.[22] At this time, there is no information re- ity in the elimination and/or dose requirements of garding a topical formulation of celecoxib. CYP2C9 substrates occur as a result.[24] Very high concentrations (3 to 9 times mean values) were ob- 2.3 Metabolism and Elimination served in 2 out of several hundred individuals receiving celecoxib, and it was suggested that they [9] Table III presents a summary of the pharmaco- had CYP2C9 deficiency. The clinical signifi-

1 cance and the underlying mechanism for these kinetic parameters of celecoxib. The t ⁄2β of celecoxib is reported to be between 11.2 and 15.6 hours pharmacokinetic differences remain unknown. and the apparent clearance (CL/F) is approxi- Individualisation of the dose may be necessary as a result. There are now many examples where mately 30 L/h (500 ml/min).[9] Celecoxib under- inborn errors of drug metabolism and racial differ- goes extensive hepatic metabolism in humans. ences in drug disposition may have clinically sig- Less than 2% is excreted unchanged in urine and nificant sequelae and account for interindividual [9,11,18] only 2.6% is excreted unchanged in faeces. variability in the dose requirement for, and response Three metabolites of celecoxib have been found to, a drug [e.g. ethanol (alcohol), warfarin, isonia- in plasma: SC-60613, SC-62087 and the glucuron- zid, phenacetin and mephenytoin].[25] ide conjugate of SC-62807. SC-60613 is the product of partial oxidation of the methyl moiety of 3.2 Specific Inhibition of celecoxib to a hydroxyl group and is a minor cir- Cyclo-Oxygenase-2 (COX-2) culating metabolite. SC-62807 (M2) is the result of It has now been determined that COX exists as complete oxidation of the methyl moiety of cele- at least 2 isoenzymes.[18,19] Generally, COX-1 is a coxib to a carboxyl group. Glucuronidation of the constitutively expressed cellular ‘house keeping’ carboxyl metabolite forms M1[9] (table I). The car- isoenzyme that is present in many tissues and reg- boxylic acid metabolite (SC-62807) constitutes ulates gastric cytoprotection, as well as vascular 19% and 54% of the dose excreted in urine and homeostasis.[26] By contrast, COX-2 is an induc- faeces, respectively, with low amounts of the glu- ible isoenzyme that is predominantly expressed in curonide metabolite also appearing in urine.[9,18] inflamed tissue although it is constitutively ex- In vitro studies using human liver microsomes pressed in parts of the brain and kidney.[27] COX-2 and heterogeneously expressed CYP protein indi- is induced by a variety of stimuli, including cyto- cate that CYP2C9 is the major isoform responsible kines, endotoxin, hormones, growth factors and for this metabolism.[18] mitogens.

It was postulated that inhibition of COX-1 re- decreased inflammatory response to arachidonic duced synthesis of cytoprotective compounds, acid but not to the mitogenic stimulator tetradec- [29] such as prostaglandin (PG) E2, whereas inhibition anylphorbol acetate. COX-2 knockout mice de- of COX-2 reduced inflammation, and that NSAIDs veloped severe nephropathy and had an altered but with a high COX-2 : COX-1 inhibitory concentra- present inflammatory response. In addition, COX- tion ratio would have the potential to cause more 2 knockout mice had increased incidence of peri- gastric erosion as the concentration required to tonitis.[30,31] It remains possible that some of the elicit beneficial effects exceeds that which causes adverse effects of NSAIDs may be related to their gastric toxicity.[10] However, some critical points ability to suppress COX-2 and that prostanoids de- regarding the COX-2 : COX-1 hypothesis can be rived via COX-1 contribute to the therapeutic action. raised: Further research derived from these transgenic an- • the results of in vitro experiments should be cau- imals may be valuable for understanding the patho- tiously related to the in vivo situation because of physiological roles of the COX isoenzymes. the pharmacokinetic properties and subsequently NSAIDs also have a ‘topical’or direct local tox- different in vivo temporal concentration profiles icity on the GI mucosa causing ulceration, which of NSAIDs in various tissues (i.e. synovium, GI is independent of COX inhibition. In contrast to tract and kidney) current nonselective NSAIDs, celecoxib is non- • in vitro experiments cannot take into account the acidic and part of its favourable tolerability profile impact of formulation may be due to both the lack of the ‘topical’ action • in vitro experiments cannot predict organ- and on GI tissues as well as the lack of inhibitory ef- tissue-specific adverse effects of NSAIDs fects on COX-1 and as yet other unidentified ef- • the relative COX-2 : COX-1 inhibitory activity fects. It is unlikely, however, that highly selective of an individual NSAID depends on the in vitro inhibitors of COX-2 will be more efficacious than system or laboratory model used nonselective NSAIDs, since many of the existing • there may be more than 2 COX-isoenzymes NSAIDs are very potent inhibitors of this isoen- • the COX-2 : COX-1 inhibitory activity is only zyme. one aspect of an individual NSAID, and other mechanisms of action in terms of anti-inflamma- 3.3 Potential of Selective Inhibitors of tory and adverse effects are possible (e.g. effects COX-2 in Prevention of Myocardial [28] on oxidative phosphorylation) Infarction, Stroke and Angina • the effects of suppression of constitutively expressed COX-2 COX-1 is the isoenzyme that mediates the anti- • in vitro experiments cannot take into account thrombotic properties of NSAIDs through inhibi- the role of prosatglandin receptors and the tissue tion of thromboxane synthesis by platelets.[32] Spe- and substrate selectivities of these receptors. cific COX-2 inhibitors do not have a therapeutic The pathogenesis of NSAID-induced GI and basis as antithrombotic agents in the context of the kidney damage has not been clearly delineated. Re- prevention of myocardial infarction and stroke. cent work using transgenic knockout mice deficient However, in patients with unstable angina, it is in the isoenzymes for COX-1 and -2 has shed light possible to have an episodic increase in thrombox- on the specific signalling roles of the 2 prostaglan- ane synthesis. This can also occur in patients with din biosynthetic pathways defined by these enzymes, unstable angina receiving aspirin, resulting in although there may be problems of extrapolating aspirin-resistant thromboxane biosynthesis.[33] Re- physiological responses in knockout mice to the cent data indicate that COX-2 is expressed in the clinical situation. Interestingly, COX-1 knockout plaques of coronary arteries and in monocytes, mice exhibited no spontaneous GI abnormalities which suggests a possible alternative mechanism, but showed decreased platelet aggregation and a i.e. that the benefits of aspirin are mediated via

[34] [14] inhibition of COX-2 activity. Thus specific of inhibition of serum thromboxane B2. Celecoxib COX-2 inhibition may have a role in protection tends to suppress the urinary excretion of 11-dehydro- against unstable angina. thromboxane B2, an index of in vivo thromboxaneA2 synthesis. In addition, celecoxib suppressed uri- 3.4 Dosage and Therapeutic Range nary excretion of the prostacyclin metabolite 2,3- dinitro-6-keto-PGF1α,anindexofsystemicpro- The usual recommended initial dosage of stacyclin biosynthesis, by a similar degree after a celecoxib for patients with osteoarthritis is 200mg single 400 and 800mg dose of celecoxib was ad- daily, administered as a single dose or as 100mg ministered. This may imply a major role for COX-2 twice daily. For patients with rheumatoid arthritis, in the biosynthesis of either systemic or renal PGI2 the recommended therapeutic dosage is 100 to under physiological conditions. COX-2 is consti- 200mg twice daily.[1] tutively expressed in the macula densa of the kid- There have been several clinical trials that sup- ney.[30] Celecoxib is not completely selective for port the use of celecoxib in pain management, in- this isoenzyme in vivo in the dose range em- [14,36] cluding 4 single dose post-third molar dental ex- ployed. The IC50 for the hydroxymethyl meta- traction studies, and 2 multiple dose (between 3 bolite against isolated recombinant human COX-1 and 5 days), post-general and orthopaedic surgical and -2 are >200 and 93.3 μg/L, respectively. The studies. Celecoxib has yet to receive FDAapproval IC50 for the carboxy metabolite against recombinant for use as analgesia, but the drug has been shown human COX-1 and -2 are >250 and 11.2 μg/L, re- to be efficacious in post-surgical dental pain at spectively.[5] doses ranging from 50 to 400mg.[3,35] A recent controlled trial of 10 days’ duration However, although celecoxib demonstrated anal- conducted in 24 healthy adults compared the ef- gesic activity in single dose dental pain studies, it fects on platelet function of a dose of celecoxib appeared to be less effective than ibuprofen or (600mg twice daily) with a standard dose of naproxen sodium at equivalent doses, and it did not naproxen (500mg twice daily). Ex vivo platelet ag- demonstrate statistically significant effectiveness gregation in response to agonists [collagen, in the treatment of pain in 2 multiple dose, 3- to 5-day arachidonate, or U46619 (a thromboxane A2 recep- post-operative trials compared with placebo.[9] tor agonist)], bleeding time, and serum thrombox- In vitro studies of celecoxib on COX-1 activity ane B2 level were measured. Naproxen produced with U937 cell microsomes, human platelets and statistically significant reductions in platelet ag- CHO cells expressing COX-1 demonstrate IC50 gregation and serum thromboxane B2 levels and values of 52 ± 9, 660 ± 20 and 320 ± 120 μg/L, increased bleeding time whereas celcoxib and pla- respectively, in protein-free media.[36] In parallel cebo did not. The results suggest that at supra- with these findings, initial studies suggest that therapeutic doses, celecoxib does not interfere with celecoxib lacks effect on COX-1 derived thrombox- platelet aggregation and haemostasis.[38] ane B2 levels in vivo and has no significant effect The effect of protein binding on the relative ac- on platelet aggregation or bleeding time.[37] Amore tivities has not been determined, but would be pre- recent study[14] has shown that at therapeutic doses dicted to increase these values (in terms of total celecoxib poorly inhibits thromboxane A2-dependent plasma or blood concentration) in proportion to the platelet aggregation induced by arachidonic acid ex degree of protein binding. vivo. Celecoxib did, however, tend to inhibit aggre- The Cmax and AUC of celecoxib are linearly re- gation by up to 10% as the dose was increased.[14] lated to dose (fig. 2).[14] There is, however, consid- Celecoxib also suppressed serum thromboxane erable variability in ex vivo COX-2 inhibition by B2 compared with placebo at the 800mg dose. It celecoxib and this relationship actually appears to appears that there is a linear relationship between be sigmoidal. A dose-response relationship for plasma concentration of celecoxib and the degree celecoxib in patients with arthritis has not yet been

30 000 r2 = 0.9938 the need for more sensitive quantitative surrogate markers of effectiveness of anti-inflammatory drugs. 20 000 There are no published data available on the ef- ( μ g/h/L)

24 fect of celecoxib on prostaglandin synthesis in hu- 10 000 man gastric mucosa, although animal studies sug- AUC gest celecoxib has no effect on the gastric production 0 [40] 0 200 400 600 800 of prostaglandins. With respect to evaluating the effectiveness of 4000 r2 = 0.9512 NSAIDs, it should be recognised that there are pos- 3000 sible ‘responders’and ‘nonresponders’to therapy.[41] ( μ g/L) 2000 Whether selective COX-2 inhibitors of celecoxib max C 1000 demonstrate this pattern of clinical response has 0 yet to be investigated. Few published studies have 0 200 400 600 800 attempted to correlate the clinical, pharmacoki- Dose (mg) netic and pharmacological data of celecoxib. Fur- Fig. 2. Relationship between dose and (top) area under the thermore, there are no data relating celecoxib con- concentration-time curve over 24 hours (AUC ) and (bottom) 24 centrations to adverse effects. However, in patients peak plasma drug concentration at 4 hours (Cmax) after administration of single doses of celecoxib to healthy volunteers.[14] who have a known allergy to sulphonamides, aspirin or NSAIDs, the use of celecoxib may be contra- [9] elucidated despite published studies which aimed indicated. As celecoxib is from a new chemical to establish such a relationship.[2,14] This is a com- class of compound it is likely that the incidence and significance of adverse effects will become more mon finding for many NSAIDs, although a linear apparent during post-marketing surveillance. relationship between anti-inflammatory actions and the dose or plasma concentration of naproxen 3.5 Effectiveness and Safety has been demonstrated in patients with rheumatoid [39] arthritis. A lack of a dose-response relationship Celecoxib has demonstrated effectiveness in for celecoxib may be because celecoxib 100 and both placebo and active-control (or comparator) 200mg twice daily is already at the upper end of clinical trials in patients with osteoarthritis and in the dose-response curve. This is supported by the patients with rheumatoid arthritis.[2,9,42-44] observation that for patients with rheumatoid ar- In moderate to severe post-operative pain fol- thritis, doses of 200 and 400mg twice daily are not lowing third molar extraction, celecoxib was supe- distinguishable from each other with respect to ef- rior to placebo in both pain relief and intensity. For fectiveness.[2,14] These doses may, therefore, be at all pharmacodynamic variables assessing pain re- [2,35] the maximum achievable clinical response. lief, celecoxib performed similarly to aspirin. It is clear that celecoxib 40mg twice daily In endoscopic studies, no significant differ- (which was significantly less active in this patient ences in ulcer or ulcer erosion was found between celecoxib and placebo. The incidence of gastric ul- group) is at the lower end of the dose-response cers and gastric erosions/ulcers was significantly curve for this drug.[1] Alternatively, these findings higher for naproxen or diclofenac than for placebo may also reflect a lack of correlation between con- or celecoxib.[1,42,45] centration and effect, but more probably suggest a A potential problem in evaluating the adverse lack of sensitivity of measured end-points, the sub- effects of new COX-2 inhibitors relates to the claim jective nature of clinical measures, the need for stud- of fewer adverse effects compared with conven- ies of greater statistical power, interpatient variability tional NSAIDs. Thus these newer drugs may be in pharmacokinetics and/or pharmacodynamics or prescribed for patients who are most prone to de-

velop such adverse effects. This has the potential renal insufficiency [glomerular filtration rate (GFR) to bias early post-marketing safety data and, along 2.04 to 2.88 L/h (34 to 48 ml/min)] than that seen with selective reporting of adverse reactions, a in individuals with normal renal function. How- product such as celecoxib may appear more rather ever, no significant relationship has been estab- than less toxic.[46,47] This phenomena has been lished between the GFR and CL/F of celecoxib.[9] termed ‘channelling’ and has the potential to com- Celecoxib is extensively metabolised and less than plicate any interpretation of the epidemiology of 1% of the drug is excreted in urine. It is possible early adverse effect reporting with the COX-2 in- that there are alterations in protein binding in renal hibitors. Nevertheless, a US FDA Arthritis Advi- impairment that may contribute to changes in he- sory Committee has recommended that the labelling patic clearance. It is also possible that there may be should include a comment saying that serious up- reduced absorption, or a compensatory increased per GI complications rates of 0.2% for celecoxib biliary excretion, when the drug is administered to and 1.7% for other NSAIDs might be expected. patients with renal impairment. However, mecha- These recommendations come after analysis of the nistic studies of these changes in renal impairment controlled clinical trials of celecoxib involving 11 000 with celecoxib are so far lacking. It is possible that [48] patients. there is reduced tubular reabsorption and/or decreased protein binding of celecoxib in renal insuf- 3.6 Disease and Celecoxib ficiency. The unbound fraction of celecoxib was not determined in the pharmacokinetic study in pa- 3.6.1 Renal Insufficiency tients with renal insufficiency and should be deter- Many patients with rheumatism have some degree mined in future studies. of renal function impairment, and elderly patients with poor renal function are especially susceptible 3.6.2 Hepatic Insufficiency to further renal impairment by NSAIDs. COX-2 The influence of chronic hepatic impairment on mRNA and immunoreactive protein localise in the celecoxib pharmacokinetics has not been com- macula densa and adjacent cortical thick ascending pletely delineated. As celecoxib undergoes signif- limb of the renal tubule of the renal cortex. Chronic icant hepatic metabolism, there may be important NaCl restriction increases the expression of this pharmacokinetic variations in patients with hepatic enzyme and appears to control renin release.[49] disorders (e.g. hepatitis, cholestasis, cirrhosis or COX-2 is also constitutively expressed in thick as- ascites). As albumin, globulin and total protein de- cending limbs and papillary interstitial cells in rats crease in patients with hepatic disease, this has the and dogs, as well as in the glomerular podocytes and potential to increase the plasma free fraction of small renal blood vessels in monkeys and humans.[49] celecoxib. It has been reported that in patients with In clinical studies, celecoxib and traditional mild and moderate (Child-Pugh class I and II) he- NSAIDs both inhibited PGE2 and 6-keto-PGF1α patic impairment the AUC of celecoxib at steady excretion and led to the development of clinically state is increased by about 40 and 180%, respec- significant oedema, worsened hypertension, in- tively, compared with healthy controls.[9] Compared creased hypophosphataemia and hydrochlorae- with matched controls, patients with moderate and mia.[9] In normotensive salt-depleted patients, the mild hepatic impairment had a significant (63 and selective inhibition of COX-2 by celecoxib causes 22%, respectively) reduction in the CL/F of cele- sodium and potassium retention and a short term coxib calculated during steady-state conditions. It transient decrease in renal blood flow and glomer- would, therefore, seem prudent that celecoxib be ular filtration rate, but had no effect on systemic administered at a reduced dosage in patients with blood pressure at a dose of 400mg.[50] moderate hepatic impairment.[9] The AUC of celecoxib has been reported to be Nearly all analgesic and anti-inflammatory approximately 47% lower in patients with chronic agents have the potential for hepatic injury. In con-

trolled clinical trials of celecoxib, the incidence of prostaglandins produced by COX-2 may be involved borderline elevations of liver function tests was 6% in regulating cellular proliferation and may be in- for celecoxib and 5% for placebo, and 0.2% of pa- volved in the initiation of the cascade of processes tients taking celecoxib and 0.3% of patients taking required for carcinogenesis, as well as aiding in placebo had notable elevations of liver enzymes tumour growth and development.[55] In addition, which resolved on cessation of treatment.[9] COX-2 has been shown to map to chromosome 1, one of the loci associated with colon cancer.[56] 3.6.3 Rheumatic Disorders The effect of rheumatoid arthritis on the phar- Preclinical studies indicate that celecoxib dem- macokinetics of celecoxib has not been reported. onstrated dose-dependent chemopreventive activ- [57-59] Fluctuations in serum albumin caused by disease ity against colon carcinogenesis. Human data processes with corresponding protein binding have not yet been published. Many of the published changes may have pharmacokinetic and pharmaco- reports on the current generation of NSAIDs and dynamic consequences for celecoxib. In addition, chemoprevention of colorectal cancer have used disease states such as rheumatoid arthritis may af- relatively high dosages that have been associated fect the capacity of the liver to metabolise cele- with significant toxicity. Long term administration coxib, possibly through the effects of inflammatory of a selective COX-2 inhibitor may be more justifi- mediators, hepatic uptake of unbound drug or mod- able. However, the ability of these drugs to inhibit ulation of intrahepatic processes. colon carcinogenesis with a relative benign toxicity profile has yet to be demonstrated. The chemo- 3.6.4 Endotoxinaemia prevention of colorectal cancer with selective in- Endotoxinaemia is associated with the expres- hibitors of COX-2 is an intriguing concept, as early sion of COX-2 and overproduction of arachidonic colonic neoplastic lesions have an excellent cure acid metabolites. Inhibition of COX-2 activity by rate, but advanced metastatic colon cancer remains selective COX-2 inhibitors, including celecoxib, incurable. However, the potential chemopreventive did not attenuate the circulatory failure nor the organ benefits of these agents must be weighed against failure caused by endotoxin in a animal model.[51] the risk of potential complications. Thus, COX-2 inhibitors may not be useful in the Colon cancer screening, using newer methods therapy of circulatory shock. It is possible that the of detecting high risk patients, deserves further generation of arachidonic acid metabolites by study since these patients could then be targeted for COX-2 is beneficial in conditions of systemic in- chemoprevention with selective COX-2 inhibitors. flammation, such as endotoxin shock, and further Further studies and clinical trials need to be done studies are required. to clarify the potential benefit of selective COX-2 3.6.5 Colorectal Cancer inhibitors in colorectal cancer and in other forms Colorectal cancer is a common malignant tumour of cancer such as lung carcinoma and skin carcino- and is a leading cause of deaths in Western coun- genesis.[60-62] tries. Reducing the morbidity and mortality of colo- In December 1999 the US FDA expanded the rectal cancer lies in its prevention and early detec- approval for celecoxib as an adjunct to usual care tion. One promising approach to chemoprevention in the management of patients with familial adeno- of these neoplasms and reduction of mortality in- matous polyposis. volves the use of NSAIDs.[52] The mechanism(s) by which NSAIDs act to re- 3.6.6 Alzheimer’s Disease duce colorectal cancer are unknown, but the obvious Evidence is mounting that NSAIDs retard the possibility is that NSAIDs inhibit COX enzymes degenerative changes associated with Alzheimer’s in the tumour. It has recently been shown that the disease.[63] Currently, the promise of NSAID use expression of COX-2 appears to increase in colo- in patients with Alzheimer’s disease relies mostly rectal adenomas and adenocarcinomas.[53,54] The on epidemiological studies that have examined

drug exposure, without detailed information about Therapeutic regimens in paediatric patients are the specific drug, dosage or duration of NSAID often inappropriately based on the extrapolation of treatment. Alzheimer’s disease is another potential pharmacokinetic data from adults. Unfortunately, target for COX-2 inhibitors, since this disease is there is no information available on the pharmaco- characterised by inflammatory processes in the kinetics or pharmacodynamics in this age group. brain that are associated with increased COX-2 The utility of celecoxib in the management of paed- expression.[16,64] iatric pyrexia and juvenile rheumatoid arthritis re- Currently, there is no information on the poten- mains unexplored. tial beneficial effects of celecoxib in the treatment of patients with Alzheimer’s disease. Celecoxib is 3.8 Pregnancy and Lactation likely to present safety advantages in elderly patients. It is not known whether the large V/F and Inhibitors of COX given during pregnancy have lipophilicity of celecoxib, which may facilitate the potential to cause adverse maternal and foetal high concentrations in the CNS compared with tra- effects. Maternal effects include the prolongation ditional NSAIDs, may influence the clinical out- of pregnancy and labour, whereas constriction of the come in the treatment of Alzheimer’s disease. ductus arteriosus, renal dysfunction and haemostatic abnormalities can occur in the foetus and neonate. In animal studies, ductus arteriosus of the foetus ex- 3.7 Influence of Age and Gender on pressed virtually only COX-1 immunoreactive Celecoxib Pharmacokinetics protein and activity. In contrast, the ductus of the term newborn pig (<45 minutes old) contained pro- Several studies have demonstrated the impor- teins of both COX-1 and -2, but the latter contrib- [17] tance of age on the pharmacokinetics and pharma- uted to >90% of PGE2 formation. A selective codynamics of NSAIDs. However, it is often diffi- COX-2 inhibitor, DuP697, reduced PGE2 levels in cult to separate the effect of age from coincident the ductus arteriosus, albeit not in plasma, but did disease states. Fluctuations in serum albumin con- not affect ductal patency in the newborn pig (<1.5 centrations and changes in severity of disease have hours old). the potential to alter the pharmacokinetics of By contrast, the COX-1 inhibitor valeryl salicy- highly bound drugs. In addition, the normal aging late, like indomethacin, markedly reduced levels of process can affect the capacity of the liver to me- PGE2 in the plasma and ductus arteriosus, causing tabolise celecoxib. In elderly individuals (over 65 significant constriction of this vessel. The ductus years of age), a 40% higher Cmax and a 50% higher arteriosus of the term newborn pig, in contrast AUC were evident at steady-state when compared with that of the foetus, expresses COX-2, but cir- with pharmacokinetic observations in young indi- culating prostaglandins, arising mostly from COX- viduals. Furthermore, in females the Cmax and AUC 1, seem to exert the major control on ductal patency are significantly higher than those found in males. in vivo.[17] and this has been attributed to lower average body- Celecoxib may be a better alternative for the weight in elderly females.[9] foetus than nonselective COX blockers for mater- In young females (<50 years) a 13% lower Cmax nal conditions such as inflammation or tocolysis. after a single dose and a longer half-life (13.9 vs Curiously, it has been suggested that in late preg- 11.4h after a single dose) was apparent compared nancy celecoxib should be avoided because it may with young males.[9] The therapeutic and toxico- cause premature closure of ductus arteriosus; how- logical implications of the changes in pharmaco- ever, no clinical studies have been published to kinetics with disease states is not known. However, support this assertion.[9] it did not appear that there were age-related increases Teratogenicity has not been found in animal in adverse experiences in clinical trials.[9] studies of celecoxib.[9] Celecoxib is excreted into

Table IV. Drugs metabolised by, inhibiting or inducing cytochrome pharmacokinetics of celecoxib demonstrate that [9,23,24] P450 (CYP) 2C9 treatment with fluconazole (but not ketoconazole) Substrates Inhibitors Inducers produced a 68% increase in Cmax and 134% in- Celecoxib Fluconazole Rifampicin (rifampin) crease in AUC, further suggesting that celecoxib Tolbutamide Ketoconazole Phenobarbital metabolism in vivo is via the CYP2C9 pathway.[17] S-Warfarin Metronidazole Carbamazepine Ibuprofen Itraconazole Ethanol In this drug interaction study with fluconazole Flurbiprofen Sulfaphenazole Secobarbital there was a decrease in Cmax for the metabolites Diclofenac Ritonavir SC-60613 and SC-62807 compared with when Phenytoin Amiodarone celecoxib was administered alone.[9] Fluoxetine Fluvastatin In vitro studies suggest that celecoxib is an in- Amitriptyline Fluvoxamine hibitor of CYP2D6 (table V) but not an inhibitor Glipizide Isoniazid of CYP2C9, 2C19 or 3A4.[9] The implication of Irbesartan Lovastatin this finding with respect to in vivo drug interac- Piroxicam Paroxetine Rosiglitazone Phenylbutazone tions remains unclear. Sulfamethoxazole Probenecid Phenytoin, an anticonvulsant, is metabolised via Tamoxifen Sertaline CYP2C9 and demonstrates a narrow therapeutic Torasemide Trimethoprim range of serum concentrations between 10 and 20 Losartan Zafirlukast mg/L. Nevertheless, coadministration of celecoxib did not alter the single dose pharmacokinetic profile of phenytoin nor the pharmacokinetics of breast milk of lactating rats at concentrations sim- [9] ilar to those in plasma. It is not yet known whether celecoxib. this pattern of excretion is extendable to humans Lithium is used to treat manic depressive epi- and if there are risks to breast-fed infants. sodes. The mean plasma concentrations of celecoxib were higher for the first 6 hours post-dose when celecoxib was coadministered with lithium than 4. Pharmacokinetic Drug Interactions when it was administered alone. The AUC of celecoxib was not significantly altered by the coadm- 4.1 Effect of Other Drugs on the inistration of lithium carbonate.[9] Pharmacokinetics of Celecoxib

Celecoxib undergoes extensive hepatic metabo- 4.2 Effect of Celecoxib on the lism in humans and in vitro studies indicate that Pharmacokinetics of Other Drugs CYP2C9 is the major isoform responsible for this NSAIDs are often coadministered with disease- [65] metabolism. CYP2C9 is an enzyme of major modifying antirheumatic drugs, such as metho- [24] importance in human drug metabolism (table IV). trexate, in patients with rheumatoid arthritis. Substrates for CYP2C9 include losartan, phenytoin, Celecoxib was studied in patients with rheumatoid tolbutamide and numerous NSAIDs. CYP2C activity in vivo is inducible by rifampicin (rifampin). [9,23,24] Evidence also indicates that the metabolism of Table V. Drugs metabolised by cytochrome P450 (CYP) 2D6 CYP2C9 substrates may be induced variably by Codeine carbamazepine, alcohol and phenobarbital.[24] Metoprolol Trazadone Clinically significant inhibition of CYP2C9 activ- Mianserin ity has been demonstrated with coadministration 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) of fluconazole, sulfaphenazole and certain other Propranolol sulphonamides.[13] The effects of multiple doses of Perphenazine fluconazole, an inhibitor of CYP2C9, or ketocon- Propafenone azole, an inhibitor of CYP3A4, on the single dose Clozapine

arthritis receiving a stable weekly oral dose of Css of lithium increased approximately 17% and methotrexate 5 to 20 mg/week for a minimum of 3 mean renal clearance was 13% lower in individuals months. The bioavailability, renal clearance and receiving lithium and celecoxib as compared with [9] tmax for total methotrexate were similar when individuals receiving lithium alone. Careful moni- celecoxib or placebo was administered with meth- toring and titration of lithium dosage is required in otrexate.[17,65] However, the power of the study was patients who receive celecoxib and lithium concur- very low and the patients studied may not be rep- rently. resentative of clinical populations. As long term NSAIDs attenuate the hypotensive response to use of celecoxib may affect renal function, and uri- several antihypertensive medications, including ACE nary excretion is an important route of elimination inhibitors, β-blockers, diuretics and vasodilators. for methotrexate, there may be a potential for re- Patients on furosemide (frusemide) or possibly duced clearance of methotrexate after the long term other diuretics should be carefully monitored if use of celecoxib. celecoxib is introduced. NSAIDs may potentiate the effect of oral anti- coagulants by a number of potential mechanisms, 5. Conclusions including altering drug metabolism, disrupting ep- ithelial integrity and independently affecting the Celecoxib is the first selective COX-2 inhibitor blood clotting system. S-Warfarin is a substrate of to be approved for clinical practice. The safety pro- CYP2C9.[24] However, steady-state concentrations file of celecoxib is promising. This may be attrib- (Css) of warfarin were not altered by the coadmin- utable to the chemical class of the compound and istration of celecoxib. Prothrombin time values its lack of acidity in addition to its COX-2 selec- were not significantly affected.[16,66] However, the tivity. The therapeutic and toxicological relevance US label of celecoxib has been altered to reflect a of celecoxib pharmacokinetic data requires further small increase in International Normalised Ratio study. There is limited information on the concen- (INR) with the coadministration of celecoxib and tration-effect relationships of celecoxib. Arelation- the need for a more intense monitoring of pro- ship between anti-inflammatory effect, analgesic thrombin times when celecoxib is commenced in a effect and plasma concentrations of the drug has patient already taking warfarin. yet to be established. There is a potential for drug Many patients with chronic arthropathies have interactions, as celecoxib is metabolised by CYP2C9, other diseases, such as diabetes and psychiatric dis- although all data to date show no significant inter- orders. Tolbutamide is a sulfonylurea antidiabetic actions with CYP2C9 substrates. agent metabolised by CYP2C9. The pharmacoki- Additional studies and post-marketing experi- netics of celecoxib were not altered by the presence ence after longer term celecoxib usage in a greater of tolbutamide, nor were the pharmacokinetics of number of patients will add substantially to the un- tolbutamide or its metabolites carboxytolbutamide derstanding of the overall risks and benefits of or hydroxytolbutamide altered by celecoxib.[9] Cele- celecoxib compared with those of the nonselective coxib does not influence the steady-state pharmaco- NSAIDs. The main clinical goal is to solve the kinetics or pharmacodynamics (blood glucose and problem of NSAID-induced GI and renal toxicity, insulin concentrations) of glibenclamide (glyburide), with the resultant morbidity and mortality, and to nor does glibenclamide affect the pharmacokinet- obtain optimal therapeutic effect with minimal ad- ics of celecoxib.[9] verse effects; celecoxib holds such promise, at least The renal clearance of lithium can be reduced by with respect to the GI tract. However, its renal ef- several NSAIDs, potentially resulting in toxic se- fects are likely to be the same as described for non- rum lithium concentrations. In healthy individuals selective NSAIDs. receiving controlled release lithium 450mg twice In view of the difficulties that have bedevilled daily with celecoxib 200mg twice daily, the mean this area of clinical investigation over the years, the

introduction of selective inhibitors of COX-2 must human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA 1999; 96: 272-7 be tempered with an additional caution that any new 15. Davies B, Morris T. Physiological parameters in laboratory an- therapeutic agent, no matter what the rationale imals and humans. Pharm Res 1993; 10: 1093-5 behind its introduction, must be carefully pre- 16. Karim A, Tolbert D, Piergies A, et al. Celecoxib, a specific COX-2 inhibitor, lacks significant drug-drug interactions scribed. True clinical superiority of the selective with methotrexate or warfarin [abstract 1698]. Arthritis COX-2 inhibitors above nonselective NSAIDs will Rheum 1998; 41 (9 Suppl.): S315 need to be demonstrated by a lower incidence of 17. Karim A, Tolbert D, Piergies A, et al. Celecoxib biotransformation: fluconazole but not ketoconazole substantially increases adverse effects that is not offset by any new clinical celecoxib exposure in man [abstract 4022]. Pharm Res 1998; pharmacokinetic or pharmacodynamic concerns. 1 Suppl. 1: S626 18. Karim A, Tolbert D, Burton E, et al. SC-58635 (celecoxib): a highly selective inhibitor of cyclooxygenase-2 disposition ki- Acknowledgements netics in man and identification of its major CYP450 isozyme in its biotransformation [abstract 3469]. Pharm Res 1997; 14 Professor Ric Day is on the Australian advisory board for Suppl. 11: S617 celecoxib. 19. Hamilton LC, Mitchell JA, Tomlinson AM, et al. Synergy between cyclo-oxygenase-2 induction and arachidonic acid supply in vivo: consequences for nonsteroidal antiinflammatory References drug efficacy. FASEB J 1999; 13: 245-51 1. Simon LS, Lanza FL, Lipsky PE, et al. Preliminary study of the 20. Day RO, Francis H, Vial J, et al. Naproxen concentrations in safety and efficacy of SC-58635, a novel cyclooxygenase-2 plasma and synovial fluid and effects on prostanoid concen- inhibitor. Arthritis Rheum 1998; 41: 1591-602 trations. J Rheumatol 1995; 22: 2295-303 2. Hubbard RC, Koepp RJ, Yu S, et al. SC-58635 (celecoxib), a 21. Henry DA. Side-effects of non-steroidal anti-inflammatory novel COX-2 selective inhibitor, is effective as a treatment drugs. Baillieres Clin Rheumatol 1988; 2: 425-54 for osteoarthritis (OA) in a short-term pilot study [abstract 22. Vaile JH, Davis P. Topical NSAIDs for musculoskeletal condi- 1188]. Arthritis Rheum 1996; 39 Suppl.: S226 tions: a review of the literature. Drugs 1998; 56: 783-99 3. Hubbard RC, Mehlisch DR, Jasper DR, et al. SC-58635, a 23. Wang SL, Huang J, Lai MD, et al. Detection of CYP2C9 poly- highly selective inhibitor of COX-2, is an effective analgesic morphism based on the polymerase chain reaction in Chinese. in an acute post-surgical pain model [abstract]. J Invest Med Pharmacogenetics 1995; 5: 37-42 1996; 44: 293A 24. Miners JP, Birkett DJ. Cytochrome P4502C9: an enzyme of 4. Zhang Y, Shaffer A, Portanova J, et al. Inhibition of cyclo- major importance in human drug metabolism. Br J Cin Phar- oxygenase-2 rapidly reverses inflammatory hyperalgesia and macol 1998; 45: 525-38 prostaglandin E production. J Pharmacol Exp Ther 1997; 2 25. Kalow W. Pharmacogenetics in biological perspective. Phar- 283: 1069-75 macol Rev 1997; 49: 369-79 5. Penning TD, Talley JJ, Bertenshaw SR, et al. Synthesis and 26. Vane JR, Mitchell JA, Appleton I, et al. Inducible isoforms of biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase and nitric-oxide synthetase in inflammation. cyclooxygenase-2 inhibitors: identification of 4-[5-(4- Proc Natl Acad Sci USA 1994; 91: 2046-50 methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzene sulfonamide (SC-58635, celecoxib). J Med Chem 1997; 40: 27. Meade EA, Smith WL, DeWitt DL. Differential inhibition of 1347-65 prostaglandin endoperoxide synthase (cyclooxygenase) iso- 6. Khanna IK, Weier JJ, Yu Y, et al. 1,2-Diarylimidazoles as po- zymes by aspirin and other non-steroidal anti-inflammatory tent, cyclooxygenase-2 selective, and orally active anti- drugs. J Biol Chem 1993; 268: 6610-4 inflammatory agents. J Med Chem 1997; 40: 1634-47 28. Mahmud T, Rafi SS, Scott DL, et al. Nonsteroidal anti- 7. Khanna IK, Weier JJ, Yu Y, et al. 1,2-Diarylimidazoles as po- inflammatory drugs and uncoupling of mitochondrial oxida- tent, and selective inhibitors of cyclooxygenase-2. J Med tive phosphorylation. Arthritis Rheum 1996; 39: 1998-2003 Chem 1997; 40: 1619-33 29. Lagenbach R, Morham SG, Tiano HF, et al. Prostaglandin syn- 8. Patterson R, Bello AE, Lefkowith J. Immunologic tolerability thase 1 gene disruption in mice reduces arachidonic acid-in- profile of celecoxib. Clin Ther 1999 Dec; 21: 2065-79 duced inflammation and indomethacin-induced gastric 9. Food and Drug Administration. New drug application #20998: ulceration. Cell 1995; 83: 483-92 clinical pharmacology/biopharmaceutics review section 30. Morham SG, Langenbach RL, Loftin CD, et al. Prostaglandin celecoxib. Bethesda (MD): FDA, 1998 synthase 2 gene disruption causes severe renal pathology in 10. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. the mouse. Cell 1995; 83: 473-82 Annu Rev Pharmacol Toxicol 1998; 38: 97-120 31. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and 11. Cryer B, Dubois A. The advent of highly selective inhibitors of an altered inflammatory response in mice lacking cyclooxy- cyclooxygenase: a review. Prost Other Lipid Mediat 1998; genase II. Nature 1995; 378: 406-9 56: 341-61 32. Schror K. Aspirin and platelets: the antiplatelet action of aspirin 12. Mitchell JA, Evans TW. Cyclooxygenase-2 as a therapeutic tar- and its role in thrombosis treatment and prophylaxis. Semin get. Inflamm Res 1998; 47 Suppl. 2: S88-92 Thromb Hemost 1997; 23: 349-56 13. Bolten WW. Scientific rationale for specific inhibition of COX- 33. Patrono C. Cyclooxygenase enzymes in human vascular dis- 2. J Rheumatol 1998; 51 Suppl.: 2-7 ease. In: Vane J, editor. Selective COX-2 inhibitors: pharmaco- 14. McAdam BF, Lawson-Catela F, Mardini IS, et al. Systemic logy, clinical effects and therapeutic potential. London: biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the Kluwer Academic Publishers, 1997

34. Baker CS, Hall RJ, Evans TJ, et al. Cyclooxygenase-2 is widely multiple organ dysfunction caused by endotoxin: a compari- expressed in atherosclerotic lesions affecting native and trans- son with dexamethasone. Br J Pharmacol 1998; 124: 586-92 planted human coronary arteries and colocalizes with induc- 52. Rosenberg L, Palmer JR, Zauber AG, et al. A hypothesis: non- ible nitric oxide synthase and nitrotyrosine particularly in steroidal anti-inflammatory drugs reduce the incidence of macrophages. Arterioscler Thromb Vasc Biol 1999; 19 (3): large bowel cancer. J Natl Cancer Inst 1996; 83: 355-8 646-55 53. Eberhardt CE, Coffey RJ, Radhika A, et al. Up regulation of 35. Mehlisch DR, Hubbard RC, Isakson P, et al. Analgesic efficacy cyclooxygenase 2 gene expression in human colorectal ade- and plasma levels of a highly selective inhibitor of COX-2 nomas and adenocarcinomas. Gastroenterology 1996; 107: (SC-58635) in patients with post-surgical dental pain [abstract 1183-8 PIII-2]. Clin Pharmacol Ther 1997; 61: 195 54. Kargman SL, O’Neill GP, Vikers PJ, et al. Expression of pros- 36. Riendeau D, Charleson S, Cromlish W, et al. Comparison of the taglandin G/H synthase-1 and -2 protein in human colorectal cyclooxygenase-1 inhibitory properties of nonsteroidal anticancer. Cancer Res 1991; 55: 2556-9 inflammatory drugs (NSAIDs) and selective COX-2 inhibi- 55. Ryseck RP, Raynoschek C, Macdonald-Bravo H, et al. Identifi- tors, using sensitive microsomal and platelet assays. Can J cation of an immediate early gene, PGHS B, whose protein Physiol Pharmacol 1997; 75: 1088-95 product has prostaglandin synthase/cyclooxygenase activity. 37. Gaw-Mengle L, Hubbard RC, Karim A, et al. A study of the Cell Gr Diff 1993; 3: 443-50 platelet effects of SC-58635, a novel COX-2 selective inhib- 56. Jones DA, Carlton DP, McIntyre TM, et al. Molecular cloning itor [abstract 374]. Arthritis Rheum 1997; 40 Suppl. 9: S93 of human prostaglandin endoperoxide synthase type II and 38. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a demonstration of expression in response to cytokines. J Biol novel cyclooxygenase-2 inhibitor, on platelet function in Chem 1993; 268: 9049-54 healthy adults: a randomized, controlled trial. J Clin Phar- 57. Kawamori T, Rao CV, Seibert K, et al. Chemopreventative ac- macol 2000; 40 (2): 124-32 tivity of celecoxib, a specific cyclooxygenase-2 inhibitor, 39. Day RO, Furst DE, Droomgoole SH, et al. Relationship of se- against colon carcinogenesis. Cancer Res 1998; 58: 409-12 rum naproxen concentration to efficacy in rheumatoid arthri- 58. Reddy BS, Rao CV, Seibert K. Evaluation of cyclooxygenase-2 tis. Clin Pharm Ther 1982; 31: 733-40 inhibitor for potential chemopreventative properties in colon 40. Anderson GD, Hauser SD, Mcgarity KL, et al. Selective inhi- carcinogenesis. Cancer Res 1996; 56: 4566-9 bition of cyclooxygenase-2 reverses inflammation and ex- 59. Masferrer J, Leahy K, Kobolt C, et al. Celecoxib: a specific pression of COX-2 and interleukin 6 in rat adjuvant arthritis. COX-2 inhibitor with anti-inflammatory, analgesic and anti- J Clin Invest 1996; 97: 2672-9 cancer activities [abstract]. Naunyn-Schmiedeberg’s Arch 41. Walker JS, Sheather-Reid RB, Carmody JJ, et al. Nonsteroidal Pharmacol 1998; 358: 8 antiinflammatory drugs in rheumatoid arthritis and osteoar- 60. Fischer SM, Lo HH, Gordon GB, et al. Chemopreventative ac- thritis: support for the concept of ‘responders’ and ‘non- tivity of celecoxib, a specific cyclooxygenase-2 inhibitor, and responders’. Arthritis Rheum 1997; 40: 1944-54 indomethacin against ultraviolet light-induced skin carcino- 42. Zhao SZ, Hatoum HT, Hubbard AC, et al. Effect of celecoxib, genesis. Mol Carcinogen 1999; 25: 231-40 a novel COX-2 inhibitor, on health-related quality of life pa- 61. Watkins DN, Lenzo JC, Segal A, et al. Expression and localiza- tients with osteoarthritis of the knee [abstract 348]. Arthritis tion of cyclo-oxygenase isoforms in non-small cell lung can- Rheum 1997; 40 suppl. 9: S88 cer. Eur Respir J 1999; 14: 412-8 43. Hubbard RC, Geis GS, Woods E, et al. Efficacy, tolerability, and 62. Kitamura Y,Shimohama S, Koike H, et al. Increased expression safety of celecoxib, a specific COX-2 inhibitor, in osteoarthri- of cyclooxygenases and peroxisome proliferator-activated tis [abstract 982]. Arthritis Rheum 1998; 41 (9 Suppl.): S196 receptor-gamma in Alzheimer’s disease brains. Biochem 44. Geis GS, Stead H, Morant S, et al. Efficacy and safety of Biophys Res Commun 1999; 254: 582-6 celecoxib, a specific COX-2 inhibitor, in patients with rheu- 63. McGeer EG, McGeer PL. The importance of inflammatory matoid arthritis [abstract 1990]. Arthritis Rheum 1998; 41 (9 mechanisms in Alzheimer disease. Exp Gerontol 1998; 33: Suppl.): S364 371-8 45. Lanza Fl, Rack MF, Callison DA, et al. Apilot endoscopic study 64. Guerguerian AM, Hardy P, Bhattacharya M, et al. Expression of the gastroduodenal effects of SC-58635, a novel COX-2 of cyclooxygenases in ductus arteriosus of fetal and newborn selective inhibitor [abstract A]. Gastroenterology 1997; 112 pigs. Am J Obstet Gynecol 1998; 179 (6 Pt 1): 1618-26 (4): 194 65. Karim A, Tolbert D, Hunt TL, et al. Celecoxib, a specific COX-2 46. Mohammed S, Croom II DW. Gastropathy due to celecoxib, a inhibitor, has no significant effect on methotrexate pharma- cyclooxygenase-2 inhibitor. N Engl J Med 1999; 340: 2005-6 cokinetics in patients with rheumatoid arthritis. J Rheumatol 47. Reuben SS, Steinberg R. Gastric perforation associated with the 1999 Dec; 26 (12): 2539-43 use of celecoxib. Anesthesiology 1999; 91: 1548-9 66. Karim A, Piergies A, Tolbert D, et al. Selective inhibitor of 48. Less GI disorders with celecoxib than conventional NSAIDs. cyclooxygenase-2 (COX-2) SC-58635 (celecoxib), does not Inpharma 1998 Dec 12; 1167: 22 affect kinetics or dynamics of warfarin [abstract 606]. J Clin 49. Khan KN, Venturini CM, Bunch RT, et al. Interspecies differ- Pharmacol 1998; 38: 880 ences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 1998; 5: 612-20 50. Rossat J, Maillard M, Nussberger J, et al. Renal effects of se- Neal M. Davies lective cyclooxygenase-2 inhibition in normotensive salt-de- Correspondence and offprints: Dr , Faculty pleted subjects. Clin Pharmacol Ther 1999; 66: 76-84 of Pharmacy, University of Sydney, Sydney, NSW 2006, 51. Leach M, Hamilton LC, Olbrich A, et al. Effects of inhibitors Australia. of the activity of cyclo-oxygenase-2 on the hypotension and E-mail: [email protected]

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