Risk management profile of etoricoxib: an example of personalized medicine

REVIEW Risk management profile of etoricoxib: an example of personalized medicine Paola Patrignani Stefania Tacconelli Marta L Capone Department of Medicine and Center of Excellence on Aging, “G. D’Annunzio” University School of Medicine, and “Gabriele D’Annunzio” University Foundation, CeSI, Chieti, Italy Correspondence: Paola Patrignani Dipartimento di Medicina e Scienze dell’Invecchiamento, Università di Chieti “G. D’Annunzio” and CeSI, Via dei Vestini 31, 66100 Chieti, Italy Tel +39 0871 3556775 Fax +39 0871 3556718 Email Abstract: The development of nonsteroidal anti-inflammatory drugs (NSAIDs) selective for cyclooxygenase (COX)-2 (named coxibs) has been driven by the aim of reducing the incidence of serious gastrointestinal (GI) adverse events associated with the administration of traditional (t) NSAIDs – mainly dependent on the inhibition of COX-1 in GI tract and platelets. However, their use has unravelled the important protective role of COX-2 for the cardiovascular (CV) system, mainly through the generation of prostacyclin. In a recent nested-case control study, we found that patients taking NSAIDs (both coxibs and tNSAIDs) had a 35% increase risk of myocardial infarction. The increased incidence of thrombotic events associated with profound inhibition of COX-2-dependent prostacyclin by coxibs and tNSAIDs can be mitigated, even if not obliterated, by a complete suppression of platelet COX-1 activity. However, most tNSAIDs and coxibs are functional COX-2 selective for the platelet (ie, they cause a profound suppression of COX-2 associated with insufficient inhibition of platelet COX-1 to translate into inhibition of platelet function), which explains their shared CV toxicity. The development of genetic and biochemical markers will help to identify the responders to NSAIDs or who are uniquely susceptible at developing thrombotic or GI events by COX inhibition. We will describe possible strategies to reduce the side effects of etoricoxib by using biochemical markers of COX inhibition, such as whole blood COX-2 and the assessment of prostacyclin biosynthesis in vivo. Keywords: etoricoxib, nonsteroidal antiinflammatory drugs, COX-2, gastrointestinal toxicity, cardiovascular toxicity, prostacyclin Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used in the general population for treating pain and inflammatory conditions (Burke et al 2006). They comprise traditional (t) NSAIDs and NSAIDs selective for cyclooxygenase (COX)-2 (named coxibs) which were developed to reduce the risk of serious gastrointestinal (GI) complications – dependent, at least in part, on the inhibition of COX-1 (FitzGerald and Patrono 2001). The therapeutic effects (analgesic and anti-inflammatory) of NSAIDs, both traditional and coxibs, are mostly due to the inhibition of COX-2-dependent prostanoids (Figure 1A). In placebo-controlled randomized clinical trials (RCTs), coxibs (rofecoxib [Vioxx ® ], celecoxib [Celebrex®, Artilog®, Solexa®, Artrid®] and valdecoxib [Bextra®]) were associated with an increase in the relative risk (RR) of cardiovascular (CV) events by 1- to 2.7-fold (Ott et al 2003; Bresalier et al 2005; Solomon et al 2005; Pfizer 2005; Nussmeier et al 2005). However, the results of observational studies and a metaanalysis of data derived from trials with coxibs have shown that the CV hazard is not restricted to NSAIDs selective for COX-2 but also applies to some tNSAIDs, such as diclofenac (Hernandez-Diaz et al 2006; Kearney et al 2006). In a recent nested-case control study, we found that patients taking NSAIDs (both coxibs Therapeutics and Clinical Risk Management 2008:4(5) 983–997 © 2008 Dove Medical Press Limited. All rights reserved 983 Patrignani et al Growth factors Tumor promoters Oncogenes Cytokines Bacterial endotoxin A Arachidonic Acid (-) tNSAIDs coxibs COX-1 (+) COX-2 Specific synthases Prostaglandin (PG)E2 PGD2 PGF2A Prostacyclin (PGI2) Thromboxane (TXA2) B The cyclooxygenase and peroxidase reactions catalyzed by COX COOH ARACHIDONIC ACID CYCLOOXYGENASE 2 O2 # # PGG2 COOH COX OOH 2 e- PEROXIDASE COOH # # PGH2 OH Figure 1 Pathways of prostanoid biosynthesis. (A) Prostanoids (PGE2, PGD2, PGF2α, PGI2, TXA2) are produced by COX-1 and COX-2 and specific synthases; (B) PGH2, generated by cyclooxygenase and peroxydase activity of COX, is then converted to prostanoids by the activity of different synthases. and tNSAIDs) had a 35% increased risk of myocardial infarction (Patrignani et al 2008a). Clinical results suggest that the CV hazard associated with the administration of NSAIDs is dose-dependent (Patrignani et al 2008a; Solomon et al 2008). In addition, the genetic background of the individual may play a role in increased susceptibility to inhibition of NSAIDs (Arehart et al 2008). To limit the possible detrimental effects, associated with the administration of this efficacious class of drugs, is necessary to develop strategies of risk management through the identification of genetic and biochemical markers to select the 984 responders to NSAIDs or who are uniquely susceptible to developing thrombotic or GI events by COX inhibition. Differential COX pathways are effective in health and disease Biology of COX-1 and COX-2 Prostanoids are lipid autacoids – including prostaglandin (PG) E2, PGF2α, PGD2, prostacyclin (PGI2), and thromboxane(TX) A2 – that are immediately released outside the cell after intracellular biosynthesis and modulate a wide variety of Therapeutics and Clinical Risk Management 2008:4(5) Etoricoxib, NSAIDs and risk management physiologic and pathologic processes via the interaction with specific receptors expressed mostly on the surface of target cells (Narumiya et al 1999; Breyer et al 2001). Under normal physiologic conditions, prostanoids play an essential homeostatic role in the GI cytoprotection, hemostasis, renal physiology, gestation, and parturition (Funk 2001; Patrono et al 2001; FitzGerald 2003). Moreover, they play important roles in pathophysiologic processes such as inflammation, cancer, and thrombosis (Funk 2001; Patrono et al 2001; FitzGerald 2003). Two isoforms of COX (COX-1 and COX-2) have been cloned and characterized (Simmons et al 2004). COX-1 and COX-2 are the products of different genes. COX-1 is considered a “housekeeping gene” by virtue of constitutive low-levels of expression in most cell types. However, high levels of constitutive expression of COX-1 have been detected in the stomach, platelets, and the kidney. In addition, COX-1 can be regulated during development (Rocca et al 1999). In contrast, the gene for COX-2 is a primary response gene with many regulatory sites; thus, COX-2 expression can be rapidly induced by bacterial endotoxin (LPS), cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α, growth factors, and the tumor promoter phorbol myristate acetate (PMA) (reviewed by Kang et al 2007). However, COX-2 is constitutively expressed in some cells in lung (Asano et al 1 (...truncated)