说明：本综述主要阐述的是塞来昔布在骨关节炎、风湿性关节炎及强直性脊柱炎中的临床应用。因篇幅较长，为了方便您阅读，我们将分为5-6期进行更新，感谢您的理解与支持。本期为此综述的第一期，主要内容：综述的摘要、前言部分，塞来昔布的药理性质。
Abstract
Celecoxib (Celebrex) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatory/analgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties.
In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400 mg/day, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.
Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs.
Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800 mg/day, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs.
Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk,
celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.
1、Introduction
NSAIDs are well established in the treatment of pain and inflammation associated with arthritis.They are believed to act predominantly by inhibiting cyclo-oxygenase (COX), a key enzyme involved in the conversion of arachidonic acid to prostaglandins (PGs) and thromboxanes.[1] PGs are prime mediators of pain and inflammation,while thromboxanes have vasoconstrictive,ypertensive and platelet activating/aggregating actions.
COX exists as at least two isoenzymes: COX-1 and COX-2.[1] COX-1 is constitutively expressed in most tissues and produces prostanoids involved in regulating physiological processes, such as haemodynamics, platelet aggregation and maintaining the integrity of the gastrointestinal (GI)mucosa. In contrast, COX-2 is an inducible enzyme,found abundantly at sites of inflammation,and produces prostanoids that primarily mediate fever, pain and inflammation.[1] However, contrary to earlier beliefs, COX-2 has been found to be constitutively expressed in certain tissues, such as the kidney, reproductive tract, brain and gastric mucosa, where it may be involved in normal physiological regulation.[2]
At therapeutic concentrations, traditional nonselective NSAIDs inhibit both COX-1 and COX-2 to varying degrees.[1] The beneficial analgesic and anti-inflammatory properties of NSAIDs are believed to result from inhibition of COX-2, while the adverse effects, particularly those on the GI tract (e.g. ulceration), are thought to result from inhibition of COX-1.[1] This ‘COX-2 hypothesis’led to the development of selective COX-2 inhibitors(coxibs) that were expected to provide the same analgesic and anti-inflammatory benefits as NSAIDs, but with substantially fewer GI adverse effects.
Celecoxib (Celebrex) was the first coxib to be introduced into clinical practice (in 1998) and was subsequently approved worldwide (under various trade names) for a variety of indications involving pain and inflammation. A subsequent coxib to be approved, rofecoxib (Vioxx), was found to be associated with an increased risk of thrombotic cardiovascular events that eventually led to the worldwide withdrawal of rofecoxib in 2004.[3]Although initial evidence suggested that the observed cardiovascular risk was possibly a class effect of selective COX-2 inhibitors, more recent data suggests that the risk may vary for different coxibs and also exists to varying degrees with traditional NSAIDs.[3]
In addition, valdecoxib (Bextra) was withdrawn from the market in 2005 as a result of cardiovascular toxicity and serious skin reactions[4] and lumiracoxib (Prexige) was restricted or withdrawn in many countries as a result of serious adverse effects on the liver.[5] As a result of these safety concerns, the use of many coxibs was restricted and, particularly as a result of the cardiovascular safety concerns, all coxibs and nonselective NSAIDs were recommended to be used only at the lowest possible dosage for the shortest possible time in order to minimize any risk.[4]
Celecoxib is currently approved in the EU for symptomatic relief in the treatment of osteoarthritis,rheumatoid arthritis and ankylosing spondylitis in adults.[6] It is approved for use in abroader range of indications in the US.[7] This article reviews the clinical efficacy and tolerability of celecoxib in the indications for which it is approved in the EU, and overviews its pharmacological properties.
2. Pharmacological Properties
The pharmacological properties of celecoxib have been reviewed previously[8,9] and are briefly overviewed in this section.
2.1 Pharmacodynamic Properties
Published values for the COX-2 selectivity of celecoxib differ depending upon the particular assay used. In an in vitro human recombinant enzyme assay, celecoxib was 375-fold more selective for COX-2 than COX-1 (50% inhibitory concentrations [IC50] 15.0 vs 0.04 mmol/L).[8] However, in an in vitro human whole blood assay,celecoxib was 30-fold more selective for COX-2 than COX-1, compared with 0.5-fold for ibuprofen,0.7-fold for naproxen, 1.9-fold for indomethacin,18-fold for meloxicam, 19-fold for nimesulide,29-fold for diclofenac and 267-fold for rofecoxib.
At the recommended therapeutic dosages of 200 or 400mg/day in healthy volunteers, celecoxib did not significantly suppress serum thromboxane B2 levels (a marker of COX-1 activity) compared with placebo, but did significantly (p < 0.01 vs placebo)inhibit lipopolysaccharide-stimulated PGE2 formation (a marker of COX-2 activity) ex vivo.[8]Celecoxib is less selective for COX-2 over COX-1 than other coxibs, such as rofecoxib, valdecoxib and lumiracoxib.[11]
Celecoxib demonstrated analgesic and antiinflammatory activities similar to those of nonselective NSAIDs (e.g. indomethacin, naproxen and piroxicam) in animal models of inflammation.[8] Supratherapeutic dosages of celecoxib did not cause injury to the GI mucosa in animal models, while celecoxib 100 or 200 mg twice daily for 7 days in human volunteers caused significantly less gastric/duodenal erosion/ulceration than naproxen and was similar to placebo.[8]
By inhibiting constitutively expressed COX-1 in platelets, NSAIDs may suppress the production of thromboxane A2 and impair platelet aggregation,which may result in an increased tendency to bleed.However, inhibition of platelet aggregation in vivo requires almost complete (>95%)inhibition of platelet COX-1 activity.[12] Even at supratherapeutic dosages (800 mg/day[13] and 1200 mg/day[14]), celecoxib produces only partial inhibition of platelet COX-1 and therefore has no effect on platelet aggregation.
Profound suppression of platelet aggregation is the basis of the cardioprotection provided by low-dose aspirin. Unlike some NSAIDs, particularly naproxen and ibuprofen, which may block the active site of COX-1, celecoxib has been shown to not interfere with the antiplatelet effects of cardioprotective low-dose aspirin.[15,16]
Inhibition of PGs with nonselective COX inhibition may result in elevated blood pressure (BP) in patients with pre-existing hypertension,particularly in hypertensive patients treated with ACE inhibitors and b-adrenergic receptor antagonists that act at least partially by increasing the synthesis of vasodilatory PGs.[17,18] Studies have indicated that, unlike rofecoxib, celecoxib does not induce significant mean increases in 24-hour systolic BP in treated hypertensive patients,but may result in some level of destabilization of hypertension control in a small proportion of patients.[17,18] However, celecoxib does significantly decrease prostacyclin production.[19] A meta-analysis of 19 trials indicated that patients taking rofecoxib have a significantly higher risk of developing hypertension than those on placebo (relative risk [RR] 2.63; 95% CI 1.42, 4.85) or NSAIDs (RR 1.78; 95% CI 1.17, 2.69), while treatment with coxibs (as a class) or etoricoxib had a nonsignificant numerical increase in risk compared with placebo (RR 1.61 [95% CI 0.91, 2.84] and RR 1.23 [95% CI 0.44, 3.44]) or NSAIDs(RR 1.25 [95% CI 0.87, 1.78] and RR 1.38 [95%CI 0.64, 2.97]).[20] In contrast, celecoxib had a nonsignificant numerically lower risk than placebo(RR 0.81; 95% CI 0.13, 5.21) or NSAIDs RR 0.82; 95% CI 0.68, 1.00).[20]
COX-2 is constitutively expressed in certain renal tissues and studies have shown that both celecoxib and NSAIDs inhibit PGE2 and 6-keto-PGF1a excretion, indicating that celecoxibmay have negative effects on renal function similar to those of NSAIDs (e.g. fluid retention and oedema).[8,9]
2.2 Pharmacokinetic Properties
Following a single celecoxib 200 mg oral dose in healthy volunteers (n = 12), one of whom was a cytochrome P450 (CYP) 2C9 poor metabolizer genotype (CYP2C9*2 orCYP2C9*3), a mean maximum plasma concentration (Cmax) of 842 mg/L was obtained after a mean time (tmax) of 2.9 hours.[21] The mean area under the plasma concentration-time curve (AUC) from time zero to infinity was 6246 mgh/L.[21] Administration of oral celecoxib with a high-fat meal delays absorption by approximately 1 hour[6] and increases total absorption by 10–20%.[7] Steady-state plasma concentrations
of celecoxib are attained within 5 days after starting therapy.[6] Celecoxib is highly protein bound (»97%) in plasma (mainly to albumin, but also to a1-acid glycoprotein) and is extensively distributed into tissues with an apparent volume of distribution at steady state of about 400 L.[6,7]
Celecoxib is primarily metabolized by CYP2C9 to three metabolites, which are inactive as inhibitors of COX-1 and COX-2.[6] After a single oral dose of radiolabelled celecoxib, 57% was eliminated in faeces and 27% in urine.[7] Celecoxib is eliminated mainly by hepatic metabolism, since<1% of the dose is excreted unchanged in the urine.[6] The apparent plasma clearance (CL/F) is approximately 500mL/min.[7] In healthy volunteers,the mean elimination half-life (t½) was 7.8 hours (range 4.6–13.1 hours); the t½ is variable and is stated in the summary of product characteristics to be 8–12 hours.[6]
Approximately 35% of Caucasians have the CYP2C9*2 or CYP2C9*3 polymorphisms that result in reduced enzyme activity and so are poor CYP2C9 metabolizers.[22] In volunteers homozygous for the CYP2C9*3 allele and administered celecoxib 200 mg once daily for 7 days, the median Cmax of celecoxib on day 7 was 4-fold higher and the median AUC from time zero to 24 hours (AUC24) was 7-fold higher than in subjects with a normal genotype (homozygous for CYP2C9*1) or a single CYP2C9*3 allele.[6] After single dose celecoxib administration, the AUC24 increased approximately 3-fold in subjects homozygous for the CYP2C9*3 allele compared with normal metabolizers.[6] As a result of this increased exposure, celecoxib should be administered with caution in these patients, and consideration should be given to reducing the dose to half the minimum recommended dose.[6]
The Cmax and AUC of celecoxib increased 53% and 26% in patients with mild hepatic impairment,and 41% and 146% in patients with moderate hepatic impairment.[6] Therefore, treatment should be initiated with half the recommended dosage in patients with moderate hepatic impairment (serum albumin 25–35 g/L) and treatment is contraindicated in those with severe hepatic impairment (serum albumin <25 g/L) [section 6].[6]
Since celecoxib is eliminated via hepatic metabolism,renal impairment is unlikely to markedly alter its pharmacokinetic properties. However,the pharmacokinetics of celecoxib have not been studied in patients with renal impairment; it should be used with caution in these patients and is contraindicated in those with severe renal impairment.[6]
The Cmax and AUC of celecoxib are increased in elderly subjects (aged ‡65 years), but dosage adjustment is not generally necessary unless bodyweight is very low.[6,7]
2.3 Potential Drug Interactions
Concomitant administration of celecoxib with the CYP2C9 inhibitor fluconazole increased the Cmax of celecoxib by 60% and the AUC by 130%,potentially increasing the risk of dose-dependent adverse events.[6] Therefore, celecoxib should be used at half the recommended dosage in patients receiving fluconazole. Concomitant use of celecoxib with CYP2C9 inhibitors should be avoided in CYP2C9 poor metabolizers.[6] CYP2C9 inducers,such as rifampicin (rifampin), carbamazepine and barbiturates, may decrease the plasma concentration of celecoxib.[6,23]
Since celecoxib is an inhibitor of CYP2D6,the dosage of CYP2D6 substrates (dextromethorphan,antidepressants, neuroleptics and antiarrhythmics)may need to be reduced when administered concomitantly with celecoxib.[6]Celecoxib also inhibits CYP2C19 in vitro and has the potential to interact with drugs metabolized by CYP2C19 (diazepam, citalopram and imipramine).[6]
Celecoxib increased the Cmax of lithium by a mean of 16% and the AUC by a mean of 18% when administered concomitantly, indicating a need to closely monitor patients on lithium therapy when concomitant celecoxib treatment is initiated or terminated.[6]
While bleeding events, some fatal, in association with increased prothrombin time have been reported,predominantly in the elderly, when celecoxib was administered concomitantly with warfarin,[6]concomitant administration of celecoxib with warfarin in healthy adult volunteers (aged 18–55 years)[n = 24] did not significantly affect the prothrombin time or steady-state pharmacokinetic parameters of S- or R-warfarin.[24] Prothrombin time should be closely monitored for the first few days when initiating or adjusting the dosage of celecoxib in patients taking warfarin.
Caution is recommended when celecoxib is used together with antihypertensive agents, particularly ACE inhibitors and angiotensin II receptor antagonists, in patients with compromised renal function, such as the elderly or dehydrated patients, since there is an increased risk of acute renal insufficiency in these patients. It is prudent to monitor renal function when first starting concomitant therapy and then intermittently thereafter.[6]
