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

Transcription

1 DRUG DISPOSITION Clin Pharmacokinet 2000 Mar; 38 (3): /00/ /$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. Day 2 and Kenneth M. Williams 2 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 Analytical Methods Pharmacokinetic Properties Absorption Distribution Distribution and Protein Binding Distribution into Synovial Fluid/Synovium Metabolism and Elimination Implications of Pharmacokinetic and Pharmacodynamic Properties for Therapeutic Use Racial and Genetic Polymorphism Specific Inhibition of Cyclo-Oxygenase-2 (COX-2) Potential of Selective Inhibitors of COX-2 in Prevention of Myocardial Infarction, Stroke and Angina Dosage and Therapeutic Range Effectiveness and Safety Disease and Celecoxib Renal Insufficiency Hepatic Insufficiency Rheumatic Disorders Endotoxinaemia Colorectal Cancer Alzheimer s Disease Influence of Age and Gender on Celecoxib Pharmacokinetics Pregnancy and Lactation Pharmacokinetic Drug Interactions Effect of Other Drugs on the Pharmacokinetics of Celecoxib Effect of Celecoxib on the Pharmacokinetics of Other Drugs Conclusions 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

2 226 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 glucuronide 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-trifluoromethyl-1H-pyrazoyl-1-yl]benzene sulphonamide, is a 1,5-diaryl-substituted pyrazole with a pka of 11.1 (fig. 1). Celecoxib (Celebrex ; Searle-Monsanto and Pfizer) was the first specific inhibitor of cyclooxygenase-2 (COX-2) to be approved by the US Food and Drug Administration (FDA), on December 31, In the treatment of patients with rheumatoid arthritis, osteoarthritis, and for management of the pain of these conditions, therapeutic doses of celecoxib have proven to be equi-efficacious when compared with other commonly used nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac, naproxen and ibuprofen. [1-3] The clinical introduction of celecoxib in 1999 has been the culmination of the important discovery of the COX isoenzymes and the subsequent search for molecules effective in selectively inhibiting COX-2 with little or no effect on COX-1. The major clinical goal was to produce an NSAID that had little or no effects on the gastrointestinal (GI) tract and kidney. In vitro assays demonstrate that celecoxib is a potent inhibitor of prostaglandin synthesis. [4] In vitro assays of inhibition of recombinant human COX-1 and -2 demonstrated that the concentrations of celecoxib required to achieve 50% inhibition of the enzyme (IC 50 )are15± 1 μg/l for COX- 1 and 0.04 ± 0.01 μg/l for COX-2. [5] In cells expressing COX-1 or -2, the IC 50 values for the COX-1 and -2 isozymes were 13 to 15 and 0.05 μg/l, respectively. [6,7] This suggests that celecoxib possesses a selectivity ratio for COX-1 : COX-2 activity of >375.

3 Celecoxib 227 NH 2 S O O the first commercially available specific COX-2 inhibitor are reviewed. 1. Analytical Methods CH 3 Fig. 1. Structure of celecoxib. N N CF 3 GI complications are the most common adverse effect of the NSAIDs. However, as celecoxib does not inhibit the enzyme COX-1 at concentrations achieved in vivo after usual clinical doses, there are putative GI safety advantages compared with other NSAIDs. As celecoxib is structurally a benzene sulphonamide (fig. 1), it should be administered with caution to patients who have demonstrated allergic-type reactions to sulphonamides. A recent meta-analysis suggests that the potential for crossallergenicity between celecoxib and the sulfanamide-containing medications appears comparable with that of placebo and other nonsulfonamide containing NSAIDs. [8] Prospective trials are needed to confirm these findings. Additionally, celecoxib should not be prescribed for patients who have asthma, urticaria or allergic-type reactions after taking aspirin (acetylsalicylic acid) or NSAIDs. [9] There are a number of general review articles [10-13] available that deal with the pharmacological properties and therapeutic indications of selective COX-2 inhibition; however, these articles do not discuss, in detail, the clinical pharmacokinetics and pharmacodynamics of celecoxib. In this article, the clinical pharmacokinetics and pharmacodynamics of To date there is only one published report describing a method for analysis of celecoxib. Plasma concentrations of celecoxib were determined by high performance liquid chromatography (HPLC) with a quantitation limit of 10 μg/l. This method involved the use of a C18 column and employed ultraviolet detection. [14] There is no information available on analysis of metabolite concentrations. 2. Pharmacokinetic Properties 2.1 Absorption Celecoxib is administered orally in conventional release capsules, with doses of 100mg and 200mg commercially available. After a single oral 200mg dose to healthy young volunteers the mean maximum drug plasma concentrations (C max ) of celecoxib were reached after between 2 and 4 hours [9] (table I). After an oral dose of 300mg, administered as a fine aqueous suspension of the 14 C-labelled drug or as a capsule, C max occurred 1.9 hours after administration. [15] Both the C max and area under the concentration-time curve (AUC) were linearly related to dose within the clinical range of 100 to 600mg. [14] Because of the lack of an intravenous form of celecoxib, apparently because of poor solubility, absolute bioavailability studies have not been conducted. Table II provides a summary of the absorption parameters [C max, time to peak concentration (t max ) and AUC] for celecoxib in both 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 Celecoxib ± ± ± ± ± ± ± ± ND ± ± 5.9 ND 49.9 ± 4.5 n = number of patients; ND = not detectable.

4 228 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 Dose (mg) n Age (y) a C max (μg/l) t max (h) AUC (μg/l h) Reference 300 ( 14 C 100μCi) NR NR ± NR NR ( 14 C 100μCi) NR NR ± (total study 80) NR 28.0 ± ± ± (total study 80) ± ± ± (total study 80) ± ± ± (total study 80) ± ± ± (total study 80) ± ± ± high fat breakfast 4 (total study 80) ± ± ± (total study 80) ± ± ± high fat breakfast 2 (total study 80) ± ± ± (total study 80) ± ± ± (total study 80) ± ± ± (total study 80) ± ± ± (17-44) ± ± ± ± ± ± ± ± ± single dose followed 48h later by bid 7 days 200 single dose followed 48h later by bid 7 days 400 single dose followed 48h later by bid 7 days ± ± ± ± ± ± ± ± ± (40-58) ± ± ± ± ± ± ± ± ± single dose followed 48h later by bid 17 days 200 single dose followed 48h later by bid 17 days 400 single dose followed 48h later by bid 17 days ± ± ± ± ± ± ± ± ± (commercial capsule) 36 NR ± ± (suspension) 36 NR (2 100 Phase II capsule) 36 NR fasting 24 NR ± ± ± high fat meal ± ± ± medium fat meal 952 ± ± ± antacid 507 ± ± ± fasting 24 NR ± ± ± fed ± ± ± fasting ± ± ± fed ± ± ± NR NR ± ± 1.2 NR bid 7 days ± ± 0.5 NR 400 daily ± ± 1.2 NR 400 single dose AM NR NR ± ± ± single dose followed 3 days later by ± ± ± at 08.00h with low fat meal 10 days 400 single dose followed 3 days later by 400 at 19.00h with low fat meal 10 days ± ± ±

5 Celecoxib 229 Table II. Contd Dose (mg) n Age (y) a C max (μg/l) t max (h) AUC (μg/l h) Reference 200 day 1, followed by 200 bid begun on day 3 and ending after a single morning dose on day < day 1, followed by 200 bid begun on day 3 and ending after a single morning dose on day > male > NR male < NR female > NR female < NR bid 5 days 24 (GFR (65-85) bid 5 days ml/min/1.73 m 2 ) bid 7 days - day 1 22 (GFR (43-78) bid 7 days - day 7 ml/min/1.73 m 2 ) day 1 followed by 100 bid 8 days - 12 mild HI (43-78) day day 1 followed by 100 bid 8 days day day 1 followed by 100 bid 8 days - 12 healthy control day day 1 followed by 100 bid 8 days day day 1 followed by 100 bid 8 days - 12 moderate HI (43-78) day day 1 followed by 100 bid 8 days day day 1 followed by 100 bid 8 days - 12 healthy control day day 1 followed by 100 bid 8 days day bid 24 NR ± ± ± bid + lithium CR 450 bid ± ± ± bid + glibenclamide 5 daily or 10 bid 10 NIDDM NR ± ± ± bid + glibenclamide 10 bid 14 NIDDM ± ± ± , day 1 17 NR ± ± ± /day, day 9 17 NR ± ± ± , day 1 + KNZ 200/day 7 days 17 NR ± ± ± , day 1 + FNZ 200/day 7 days 17 NR ± ± ± (21-49) ± ± ± ± ± ± ± ± ± a Mean age; range in parentheses. AUC = area under the concentration-time curve; bid = twice daily; C max = 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; t max = time taken to achieve C max. In single dose studies, coadministration of a high fat (75g) meal led to a delay in the C max of between 1 and 2 hours and the AUC was increased significantly, by 10 to 20%, compared with fasting conditions. [9] Coadministration of celecoxib with aluminium- or magnesium-containing antacids resulted in a 37% decrease in the C max and a 10% decrease in AUC. [9]

6 230 Davies et al. 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 Dose (mg) n Age (y) a t1 2β (h) V/F (L/kg) CL/F (L/h) Reference 300 ( 14 C 100μCi) NR NR 15.6 NR NR ( 14 C 100μCi) NR NR NR NR NR 5 4 (total study 80) NR 4.5 ± 0.8 NR NR (total study 80) 10.3 ± 3.8 NR NR 50 4 (total study 80) 7.7 ± 2.7 NR NR (total study 80) 8.5 ± 2.9 NR NR (total study 80) 7.6 ± 5.6 NR NR high fat breakfast 4 (total study 80) 9.5 ± 5.6 NR NR (total study 80) 7.5 ± 2.4 NR NR high fat breakfast 2 (total study 80) 4.2 ± 2.3 NR NR (total study 80) 9.6 ± 3.7 NR NR (total study 80) 10.9 ± 5.2 NR NR (total study 80) 16.4 ± 17.3 NR NR 40 8 (17-44) 4.2 ± ± ± ± ± ± ± ± ± single dose followed 48h later by bid 7 days ± ± ± single dose followed 48h later by bid 7 days ± ± ± single dose followed 48h later by bid 7 days ± ± ± (40-58) 7.7 ± ± ± ± ± ± ± ± ± single dose followed 48h later by bid 17 days 7.4 ± ± ± single dose followed 48h later by bid 17 days 12.1 ± ± ± single dose followed 48h later by bid 17 days 14.2 ± ± ± (commercial capsule) 36 NR 11.9 NR (suspension) 36 NR 13.3 NR (2 100 Phase II capsule) 36 NR 14.0 NR fasting 24 NR 14.1 ± 11.4 NR NR 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 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 and ending after a single morning dose on day < day 1, followed by 200 bid begun on day 3 and ending after a single morning dose on day > male >65 NR NR male <50 NR NR female >65 NR NR female <50 NR NR

7 Celecoxib 231 Table III. Contd Dose (mg) n Age (y) a t1 2β (h) V/F (L/kg) CL/F (L/h) Reference 200 bid 5 days 24 (GFR (65-85) NR NR bid 5 days ml/min/1.73 m 2 ) NR NR bid 7 days - day 1 22 (GFR NR NR NR bid 7 days - day 7 ml/min/1.73 m 2 ) NR NR day 1 followed by 100 bid 8 days - day 1 12 mild HI (43-78) 11.2 NR day 1 followed by 100 bid 8 days - day NR day 1 followed by 100 bid 8 days - day 1 12 healthy controls 10.8 NR day 1 followed by 100 bid 8 days - day NR day 1 followed by 100 bid 8 days - day 1 12 moderate HI (43-78) 14.0 NR day 1 followed by 100 bid 8 days - day NR day 1 followed by 100 bid 8 days - day 1 12 healthy controls 11.0 NR day 1 followed by 100 bid 8 days - day NR day 1 17 NR 9.6 NR NR /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 Distribution and Protein Binding Most traditional NSAIDs are highly (>98%) protein bound to albumin and have an apparent volume of distribution (V/F) ranging from 0.1 to 0.3 L/kg. This volume of distribution is much lower than the volume of total body water (0.6 L/kg) and is equivalent to plasma or blood volume. [15] Celecoxib is also extensively (>97%) protein bound, primarily to albumin. The fraction of unbound drug remains essentially constant (mean 2.6% unbound) at total plasma celecoxib concentrations up to 4000 μg/l. [9] Based on measurement of total 14 C radioactivity, celecoxib is evenly distributed between erythrocytes and plasma (red blood cell/plasma = 0.89). [18] Celecoxib has an V/F of 455 ± 166L in humans (5.7 to 7.1 L/kg) [table II]. [9,18] This larger than expected V/F when compared with other NSAIDs may relate to the lipophilic nature of celecoxib or be reflective of a low bioavailability Distribution into Synovial Fluid/Synovium Recent preclinical studies suggest that increased prostanoid production in inflammation requires increased COX-2 expression and increased substrate, arachidonic acid. The supply of arachidonic acid to COX-2 may determine the effectiveness of NSAIDs, as supplying arachidonic acid leads to increased prostanoid production and subsequently reduces the effectiveness of NSAIDs, including selective COX-2 inhibitors. [19] NSAIDs may inhibit prostanoid production in a manner that is inversely related to arachidonic acid supply. It has been suggested that COX-2 inhibitors are less effective at more inflamed sites where phospholipasea 2 activity is increased. [19] This may provide a rational explanation for the observation that higher dosages of celecoxib are required for the management of patients with rheumatoid arthritis as compared with patients with osteoarthritis. [20] The distribution of specific COX-2 inhibitors into the synovium may be an extremely important determinant of the effectiveness of this class of compounds. However, there are no published data on either synovial fluid or synovium concentrations of celecoxib. Based on the relatively high protein binding and intermediate elimination half-life (t1 2β), one might expect the relative distribution between blood and synovial fluid to be similar to the synovial fluid concentrations displayed by naproxen. [20]

8 232 Davies et al. The impact of the lipophilic properties of celecoxib on trans-synovial transport is unclear. NSAIDs account for a high percentage of reported serious adverse drug reactions. [21] As a consequence, there has been considerable interest in the development of topical NSAIDs in recent years with the aim of providing local action without systemic adverse effects. When applied topically, these drugs are formulated to penetrate the skin barrier in sufficient amounts to reach the subadjacent joints and muscles and exert therapeutic activity. Local enhanced topical delivery may also allow the clinician to deliver a specific COX-2 inhibitor to the site of action and increase the therapeutic ratio even further. [22] At this time, there is no information regarding a topical formulation of celecoxib. 2.3 Metabolism and Elimination Table III presents a summary of the pharmacokinetic parameters of celecoxib. The t1 2β of celecoxib is reported to be between 11.2 and 15.6 hours and the apparent clearance (CL/F) is approximately 30 L/h (500 ml/min). [9] Celecoxib undergoes extensive hepatic metabolism in humans. Less than 2% is excreted unchanged in urine and only 2.6% is excreted unchanged in faeces. [9,11,18] Three metabolites of celecoxib have been found in plasma: SC-60613, SC and the glucuronide conjugate of SC SC is the product of partial oxidation of the methyl moiety of celecoxib to a hydroxyl group and is a minor circulating metabolite. SC (M2) is the result of complete oxidation of the methyl moiety of celecoxib to a carboxyl group. Glucuronidation of the carboxyl metabolite forms M1 [9] (table I). The carboxylic acid metabolite (SC-62807) constitutes 19% and 54% of the dose excreted in urine and faeces, respectively, with low amounts of the glucuronide metabolite also appearing in urine. [9,18] In vitro studies using human liver microsomes and heterogeneously expressed CYP protein indicate that CYP2C9 is the major isoform responsible for this metabolism. [18] 3. Implications of Pharmacokinetic and Pharmacodynamic Properties for Therapeutic Use 3.1 Racial and Genetic Polymorphism A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC and 11% lower CL/F of celecoxib in Blacks compared with Caucasians. [9] The reason for these pharmacokinetic differences is unclear. Variants at several amino acid residues lead to genetic polymorphism in the coding region of the CYP2C9 gene. [23] Markedly diminished metabolic capacity for CYP2C9 substrates and wide variability in the elimination and/or dose requirements of CYP2C9 substrates occur as a result. [24] Very high concentrations (3 to 9 times mean values) were observed in 2 out of several hundred individuals receiving celecoxib, and it was suggested that they had CYP2C9 deficiency. [9] The clinical significance and the underlying mechanism for these pharmacokinetic differences remain unknown. Individualisation of the dose may be necessary as a result. There are now many examples where inborn errors of drug metabolism and racial differences in drug disposition may have clinically significant sequelae and account for interindividual variability in the dose requirement for, and response to, a drug [e.g. ethanol (alcohol), warfarin, isoniazid, phenacetin and mephenytoin]. [25] 3.2 Specific Inhibition of Cyclo-Oxygenase-2 (COX-2) It has now been determined that COX exists as at least 2 isoenzymes. [18,19] Generally, COX-1 is a constitutively expressed cellular house keeping isoenzyme that is present in many tissues and regulates gastric cytoprotection, as well as vascular homeostasis. [26] By contrast, COX-2 is an inducible isoenzyme that is predominantly expressed in inflamed tissue although it is constitutively expressed in parts of the brain and kidney. [27] COX-2 is induced by a variety of stimuli, including cytokines, endotoxin, hormones, growth factors and mitogens.

9 Celecoxib 233 It was postulated that inhibition of COX-1 reduced synthesis of cytoprotective compounds, such as prostaglandin (PG) E 2, whereas inhibition of COX-2 reduced inflammation, and that NSAIDs with a high COX-2 : COX-1 inhibitory concentration ratio would have the potential to cause more gastric erosion as the concentration required to elicit beneficial effects exceeds that which causes gastric toxicity. [10] However, some critical points regarding the COX-2 : COX-1 hypothesis can be raised: the results of in vitro experiments should be cautiously related to the in vivo situation because of the pharmacokinetic properties and subsequently different in vivo temporal concentration profiles of NSAIDs in various tissues (i.e. synovium, GI tract and kidney) in vitro experiments cannot take into account the impact of formulation in vitro experiments cannot predict organ- and tissue-specific adverse effects of NSAIDs the relative COX-2 : COX-1 inhibitory activity of an individual NSAID depends on the in vitro system or laboratory model used there may be more than 2 COX-isoenzymes the COX-2 : COX-1 inhibitory activity is only one aspect of an individual NSAID, and other mechanisms of action in terms of anti-inflammatory and adverse effects are possible (e.g. effects on oxidative phosphorylation) [28] the effects of suppression of constitutively expressed COX-2 in vitro experiments cannot take into account the role of prosatglandin receptors and the tissue and substrate selectivities of these receptors. The pathogenesis of NSAID-induced GI and kidney damage has not been clearly delineated. Recent work using transgenic knockout mice deficient in the isoenzymes for COX-1 and -2 has shed light on the specific signalling roles of the 2 prostaglandin biosynthetic pathways defined by these enzymes, although there may be problems of extrapolating physiological responses in knockout mice to the clinical situation. Interestingly, COX-1 knockout mice exhibited no spontaneous GI abnormalities but showed decreased platelet aggregation and a decreased inflammatory response to arachidonic acid but not to the mitogenic stimulator tetradecanylphorbol acetate. [29] COX-2 knockout mice developed severe nephropathy and had an altered but present inflammatory response. In addition, COX- 2 knockout mice had increased incidence of peritonitis. [30,31] It remains possible that some of the adverse effects of NSAIDs may be related to their ability to suppress COX-2 and that prostanoids derived via COX-1 contribute to the therapeutic action. Further research derived from these transgenic animals may be valuable for understanding the pathophysiological roles of the COX isoenzymes. NSAIDs also have a topical or direct local toxicity on the GI mucosa causing ulceration, which is independent of COX inhibition. In contrast to current nonselective NSAIDs, celecoxib is nonacidic and part of its favourable tolerability profile may be due to both the lack of the topical action on GI tissues as well as the lack of inhibitory effects on COX-1 and as yet other unidentified effects. It is unlikely, however, that highly selective inhibitors of COX-2 will be more efficacious than nonselective NSAIDs, since many of the existing NSAIDs are very potent inhibitors of this isoenzyme. 3.3 Potential of Selective Inhibitors of COX-2 in Prevention of Myocardial Infarction, Stroke and Angina COX-1 is the isoenzyme that mediates the antithrombotic properties of NSAIDs through inhibition of thromboxane synthesis by platelets. [32] Specific COX-2 inhibitors do not have a therapeutic basis as antithrombotic agents in the context of the prevention of myocardial infarction and stroke. However, in patients with unstable angina, it is possible to have an episodic increase in thromboxane synthesis. This can also occur in patients with unstable angina receiving aspirin, resulting in aspirin-resistant thromboxane biosynthesis. [33] Recent data indicate that COX-2 is expressed in the plaques of coronary arteries and in monocytes, which suggests a possible alternative mechanism, i.e. that the benefits of aspirin are mediated via

10 234 Davies et al. inhibition of COX-2 activity. [34] Thus specific COX-2 inhibition may have a role in protection against unstable angina. 3.4 Dosage and Therapeutic Range The usual recommended initial dosage of celecoxib for patients with osteoarthritis is 200mg daily, administered as a single dose or as 100mg twice daily. For patients with rheumatoid arthritis, the recommended therapeutic dosage is 100 to 200mg twice daily. [1] There have been several clinical trials that support the use of celecoxib in pain management, including 4 single dose post-third molar dental extraction studies, and 2 multiple dose (between 3 and 5 days), post-general and orthopaedic surgical studies. Celecoxib has yet to receive FDA approval for use as analgesia, but the drug has been shown to be efficacious in post-surgical dental pain at doses ranging from 50 to 400mg. [3,35] However, although celecoxib demonstrated analgesic activity in single dose dental pain studies, it appeared to be less effective than ibuprofen or naproxen sodium at equivalent doses, and it did not demonstrate statistically significant effectiveness in the treatment of pain in 2 multiple dose, 3- to 5-day post-operative trials compared with placebo. [9] In vitro studies of celecoxib on COX-1 activity with U937 cell microsomes, human platelets and CHO cells expressing COX-1 demonstrate IC 50 values of 52 ± 9, 660 ± 20 and 320 ± 120 μg/l, respectively, in protein-free media. [36] In parallel with these findings, initial studies suggest that celecoxib lacks effect on COX-1 derived thromboxane B 2 levels in vivo and has no significant effect on platelet aggregation or bleeding time. [37] Amore recent study [14] has shown that at therapeutic doses celecoxib poorly inhibits thromboxane A 2 -dependent platelet aggregation induced by arachidonic acid ex vivo. Celecoxib did, however, tend to inhibit aggregation by up to 10% as the dose was increased. [14] Celecoxib also suppressed serum thromboxane B 2 compared with placebo at the 800mg dose. It appears that there is a linear relationship between plasma concentration of celecoxib and the degree of inhibition of serum thromboxane B 2. [14] Celecoxib tends to suppress the urinary excretion of 11-dehydrothromboxane B 2, an index of in vivo thromboxane A 2 synthesis. In addition, celecoxib suppressed urinary excretion of the prostacyclin metabolite 2,3- dinitro-6-keto-pgf 1α,anindexofsystemicprostacyclin biosynthesis, by a similar degree after a single 400 and 800mg dose of celecoxib was administered. This may imply a major role for COX-2 in the biosynthesis of either systemic or renal PGI 2 under physiological conditions. COX-2 is constitutively expressed in the macula densa of the kidney. [30] Celecoxib is not completely selective for this isoenzyme in vivo in the dose range employed. [14,36] The IC 50 for the hydroxymethyl metabolite against isolated recombinant human COX-1 and -2 are >200 and 93.3 μg/l, respectively. The IC 50 for the carboxy metabolite against recombinant human COX-1 and -2 are >250 and 11.2 μg/l, respectively. [5] A recent controlled trial of 10 days duration conducted in 24 healthy adults compared the effects on platelet function of a dose of celecoxib (600mg twice daily) with a standard dose of naproxen (500mg twice daily). Ex vivo platelet aggregation in response to agonists [collagen, arachidonate, or U46619 (a thromboxane A 2 receptor agonist)], bleeding time, and serum thromboxane B 2 level were measured. Naproxen produced statistically significant reductions in platelet aggregation and serum thromboxane B 2 levels and increased bleeding time whereas celcoxib and placebo did not. The results suggest that at supratherapeutic doses, celecoxib does not interfere with platelet aggregation and haemostasis. [38] The effect of protein binding on the relative activities has not been determined, but would be predicted to increase these values (in terms of total plasma or blood concentration) in proportion to the degree of protein binding. The C max and AUC of celecoxib are linearly related to dose (fig. 2). [14] There is, however, considerable variability in ex vivo COX-2 inhibition by celecoxib and this relationship actually appears to be sigmoidal. A dose-response relationship for celecoxib in patients with arthritis has not yet been

11 Celecoxib 235 AUC 24 (μg/h/l) C max (μg/l) r 2 = r 2 = Dose (mg) Fig. 2. Relationship between dose and (top) area under the concentration-time curve over 24 hours (AUC 24) and (bottom) peak plasma drug concentration at 4 hours (C max) after administration of single doses of celecoxib to healthy volunteers. [14] elucidated despite published studies which aimed to establish such a relationship. [2,14] This is a common finding for many NSAIDs, although a linear relationship between anti-inflammatory actions and the dose or plasma concentration of naproxen has been demonstrated in patients with rheumatoid arthritis. [39] A lack of a dose-response relationship for celecoxib may be because celecoxib 100 and 200mg twice daily is already at the upper end of the dose-response curve. This is supported by the observation that for patients with rheumatoid arthritis, doses of 200 and 400mg twice daily are not distinguishable from each other with respect to effectiveness. [2,14] These doses may, therefore, be at the maximum achievable clinical response. It is clear that celecoxib 40mg twice daily (which was significantly less active in this patient group) is at the lower end of the dose-response curve for this drug. [1] Alternatively, these findings may also reflect a lack of correlation between concentration and effect, but more probably suggest a lack of sensitivity of measured end-points, the subjective nature of clinical measures, the need for studies of greater statistical power, interpatient variability in pharmacokinetics and/or pharmacodynamics or the need for more sensitive quantitative surrogate markers of effectiveness of anti-inflammatory drugs. There are no published data available on the effect of celecoxib on prostaglandin synthesis in human gastric mucosa, although animal studies suggest celecoxib has no effect on the gastric production of prostaglandins. [40] With respect to evaluating the effectiveness of NSAIDs, it should be recognised that there are possible responders and nonresponders to therapy. [41] Whether selective COX-2 inhibitors of celecoxib demonstrate this pattern of clinical response has yet to be investigated. Few published studies have attempted to correlate the clinical, pharmacokinetic and pharmacological data of celecoxib. Furthermore, there are no data relating celecoxib concentrations to adverse effects. However, in patients who have a known allergy to sulphonamides, aspirin or NSAIDs, the use of celecoxib may be contraindicated. [9] As celecoxib is from a new chemical class of compound it is likely that the incidence and significance of adverse effects will become more apparent during post-marketing surveillance. 3.5 Effectiveness and Safety Celecoxib has demonstrated effectiveness in both placebo and active-control (or comparator) clinical trials in patients with osteoarthritis and in patients with rheumatoid arthritis. [2,9,42-44] In moderate to severe post-operative pain following third molar extraction, celecoxib was superior to placebo in both pain relief and intensity. For all pharmacodynamic variables assessing pain relief, celecoxib performed similarly to aspirin. [2,35] In endoscopic studies, no significant differences in ulcer or ulcer erosion was found between celecoxib and placebo. The incidence of gastric ulcers and gastric erosions/ulcers was significantly higher for naproxen or diclofenac than for placebo or celecoxib. [1,42,45] A potential problem in evaluating the adverse effects of new COX-2 inhibitors relates to the claim of fewer adverse effects compared with conventional NSAIDs. Thus these newer drugs may be prescribed for patients who are most prone to de-

12 236 Davies et al. velop such adverse effects. This has the potential to bias early post-marketing safety data and, along with selective reporting of adverse reactions, a product such as celecoxib may appear more rather than less toxic. [46,47] This phenomena has been termed channelling and has the potential to complicate any interpretation of the epidemiology of early adverse effect reporting with the COX-2 inhibitors. Nevertheless, a US FDA Arthritis Advisory Committee has recommended that the labelling should include a comment saying that serious upper GI complications rates of 0.2% for celecoxib and 1.7% for other NSAIDs might be expected. These recommendations come after analysis of the controlled clinical trials of celecoxib involving patients. [48] 3.6 Disease and Celecoxib Renal Insufficiency Many patients with rheumatism have some degree of renal function impairment, and elderly patients with poor renal function are especially susceptible to further renal impairment by NSAIDs. COX-2 mrna and immunoreactive protein localise in the macula densa and adjacent cortical thick ascending limb of the renal tubule of the renal cortex. Chronic NaCl restriction increases the expression of this enzyme and appears to control renin release. [49] COX-2 is also constitutively expressed in thick ascending limbs and papillary interstitial cells in rats and dogs, as well as in the glomerular podocytes and small renal blood vessels in monkeys and humans. [49] In clinical studies, celecoxib and traditional NSAIDs both inhibited PGE 2 and 6-keto-PGF 1α excretion and led to the development of clinically significant oedema, worsened hypertension, increased hypophosphataemia and hydrochloraemia. [9] In normotensive salt-depleted patients, the selective inhibition of COX-2 by celecoxib causes sodium and potassium retention and a short term transient decrease in renal blood flow and glomerular filtration rate, but had no effect on systemic blood pressure at a dose of 400mg. [50] The AUC of celecoxib has been reported to be approximately 47% lower in patients with chronic renal insufficiency [glomerular filtration rate (GFR) 2.04 to 2.88 L/h (34 to 48 ml/min)] than that seen in individuals with normal renal function. However, no significant relationship has been established between the GFR and CL/F of celecoxib. [9] Celecoxib is extensively metabolised and less than 1% of the drug is excreted in urine. It is possible that there are alterations in protein binding in renal impairment that may contribute to changes in hepatic clearance. It is also possible that there may be reduced absorption, or a compensatory increased biliary excretion, when the drug is administered to patients with renal impairment. However, mechanistic studies of these changes in renal impairment with celecoxib are so far lacking. It is possible that there is reduced tubular reabsorption and/or decreased protein binding of celecoxib in renal insufficiency. The unbound fraction of celecoxib was not determined in the pharmacokinetic study in patients with renal insufficiency and should be determined in future studies Hepatic Insufficiency The influence of chronic hepatic impairment on celecoxib pharmacokinetics has not been completely delineated. As celecoxib undergoes significant hepatic metabolism, there may be important pharmacokinetic variations in patients with hepatic disorders (e.g. hepatitis, cholestasis, cirrhosis or ascites). As albumin, globulin and total protein decrease in patients with hepatic disease, this has the potential to increase the plasma free fraction of celecoxib. It has been reported that in patients with mild and moderate (Child-Pugh class I and II) hepatic impairment the AUC of celecoxib at steady state is increased by about 40 and 180%, respectively, compared with healthy controls. [9] Compared with matched controls, patients with moderate and mild hepatic impairment had a significant (63 and 22%, respectively) reduction in the CL/F of celecoxib calculated during steady-state conditions. It would, therefore, seem prudent that celecoxib be administered at a reduced dosage in patients with moderate hepatic impairment. [9] Nearly all analgesic and anti-inflammatory agents have the potential for hepatic injury. In con-

13 Celecoxib 237 trolled clinical trials of celecoxib, the incidence of borderline elevations of liver function tests was 6% for celecoxib and 5% for placebo, and 0.2% of patients taking celecoxib and 0.3% of patients taking placebo had notable elevations of liver enzymes which resolved on cessation of treatment. [9] Rheumatic Disorders The effect of rheumatoid arthritis on the pharmacokinetics of celecoxib has not been reported. Fluctuations in serum albumin caused by disease processes with corresponding protein binding changes may have pharmacokinetic and pharmacodynamic consequences for celecoxib. In addition, disease states such as rheumatoid arthritis may affect the capacity of the liver to metabolise celecoxib, possibly through the effects of inflammatory mediators, hepatic uptake of unbound drug or modulation of intrahepatic processes Endotoxinaemia Endotoxinaemia is associated with the expression of COX-2 and overproduction of arachidonic acid metabolites. Inhibition of COX-2 activity by selective COX-2 inhibitors, including celecoxib, did not attenuate the circulatory failure nor the organ failure caused by endotoxin in a animal model. [51] Thus, COX-2 inhibitors may not be useful in the therapy of circulatory shock. It is possible that the generation of arachidonic acid metabolites by COX-2 is beneficial in conditions of systemic inflammation, such as endotoxin shock, and further studies are required Colorectal Cancer Colorectal cancer is a common malignant tumour and is a leading cause of deaths in Western countries. Reducing the morbidity and mortality of colorectal cancer lies in its prevention and early detection. One promising approach to chemoprevention of these neoplasms and reduction of mortality involves the use of NSAIDs. [52] The mechanism(s) by which NSAIDs act to reduce colorectal cancer are unknown, but the obvious possibility is that NSAIDs inhibit COX enzymes in the tumour. It has recently been shown that the expression of COX-2 appears to increase in colorectal adenomas and adenocarcinomas. [53,54] The prostaglandins produced by COX-2 may be involved in regulating cellular proliferation and may be involved in the initiation of the cascade of processes required for carcinogenesis, as well as aiding in tumour growth and development. [55] In addition, COX-2 has been shown to map to chromosome 1, one of the loci associated with colon cancer. [56] Preclinical studies indicate that celecoxib demonstrated dose-dependent chemopreventive activity against colon carcinogenesis. [57-59] Human data have not yet been published. Many of the published reports on the current generation of NSAIDs and chemoprevention of colorectal cancer have used relatively high dosages that have been associated with significant toxicity. Long term administration of a selective COX-2 inhibitor may be more justifiable. However, the ability of these drugs to inhibit colon carcinogenesis with a relative benign toxicity profile has yet to be demonstrated. The chemoprevention of colorectal cancer with selective inhibitors of COX-2 is an intriguing concept, as early colonic neoplastic lesions have an excellent cure rate, but advanced metastatic colon cancer remains incurable. However, the potential chemopreventive benefits of these agents must be weighed against the risk of potential complications. Colon cancer screening, using newer methods of detecting high risk patients, deserves further study since these patients could then be targeted for chemoprevention with selective COX-2 inhibitors. Further studies and clinical trials need to be done to clarify the potential benefit of selective COX-2 inhibitors in colorectal cancer and in other forms of cancer such as lung carcinoma and skin carcinogenesis. [60-62] In December 1999 the US FDA expanded the approval for celecoxib as an adjunct to usual care in the management of patients with familial adenomatous polyposis Alzheimer s Disease Evidence is mounting that NSAIDs retard the degenerative changes associated with Alzheimer s disease. [63] Currently, the promise of NSAID use in patients with Alzheimer s disease relies mostly on epidemiological studies that have examined

14 238 Davies et al. drug exposure, without detailed information about the specific drug, dosage or duration of NSAID treatment. Alzheimer s disease is another potential target for COX-2 inhibitors, since this disease is characterised by inflammatory processes in the brain that are associated with increased COX-2 expression. [16,64] Currently, there is no information on the potential beneficial effects of celecoxib in the treatment of patients with Alzheimer s disease. Celecoxib is likely to present safety advantages in elderly patients. It is not known whether the large V/F and lipophilicity of celecoxib, which may facilitate high concentrations in the CNS compared with traditional NSAIDs, may influence the clinical outcome in the treatment of Alzheimer s disease. 3.7 Influence of Age and Gender on Celecoxib Pharmacokinetics Several studies have demonstrated the importance of age on the pharmacokinetics and pharmacodynamics of NSAIDs. However, it is often difficult to separate the effect of age from coincident disease states. Fluctuations in serum albumin concentrations and changes in severity of disease have the potential to alter the pharmacokinetics of highly bound drugs. In addition, the normal aging process can affect the capacity of the liver to metabolise celecoxib. In elderly individuals (over 65 years of age), a 40% higher C max and a 50% higher AUC were evident at steady-state when compared with pharmacokinetic observations in young individuals. Furthermore, in females the C max and AUC are significantly higher than those found in males. and this has been attributed to lower average bodyweight in elderly females. [9] In young females (<50 years) a 13% lower C max after a single dose and a longer half-life (13.9 vs 11.4h after a single dose) was apparent compared with young males. [9] The therapeutic and toxicological implications of the changes in pharmacokinetics with disease states is not known. However, it did not appear that there were age-related increases in adverse experiences in clinical trials. [9] Therapeutic regimens in paediatric patients are often inappropriately based on the extrapolation of pharmacokinetic data from adults. Unfortunately, there is no information available on the pharmacokinetics or pharmacodynamics in this age group. The utility of celecoxib in the management of paediatric pyrexia and juvenile rheumatoid arthritis remains unexplored. 3.8 Pregnancy and Lactation Inhibitors of COX given during pregnancy have the potential to cause adverse maternal and foetal effects. Maternal effects include the prolongation of pregnancy and labour, whereas constriction of the ductus arteriosus, renal dysfunction and haemostatic abnormalities can occur in the foetus and neonate. In animal studies, ductus arteriosus of the foetus expressed virtually only COX-1 immunoreactive protein and activity. In contrast, the ductus of the term newborn pig (<45 minutes old) contained proteins of both COX-1 and -2, but the latter contributed to >90% of PGE 2 formation. [17] A selective COX-2 inhibitor, DuP697, reduced PGE 2 levels in the ductus arteriosus, albeit not in plasma, but did not affect ductal patency in the newborn pig (<1.5 hours old). By contrast, the COX-1 inhibitor valeryl salicylate, like indomethacin, markedly reduced levels of PGE 2 in the plasma and ductus arteriosus, causing significant constriction of this vessel. The ductus arteriosus of the term newborn pig, in contrast with that of the foetus, expresses COX-2, but circulating prostaglandins, arising mostly from COX- 1, seem to exert the major control on ductal patency in vivo. [17] Celecoxib may be a better alternative for the foetus than nonselective COX blockers for maternal conditions such as inflammation or tocolysis. Curiously, it has been suggested that in late pregnancy celecoxib should be avoided because it may cause premature closure of ductus arteriosus; however, no clinical studies have been published to support this assertion. [9] Teratogenicity has not been found in animal studies of celecoxib. [9] Celecoxib is excreted into