Start of new generation of NSAIDs?

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1 Vet Times The website for the veterinary profession Start of new generation of NSAIDs? Author : Peter Lees Categories : Vets Date : May 16, 2011 Peter Lees discusses development of robenacoxib, an NSAID with high COX-2 selectivity NSAIDS are the single most commonly prescribed drugs in small animal medicine, yet a significant percentage of the side effects and adverse events recorded annually by the VMD can be directly attributed to their use. This article will discuss the properties of NSAIDs as they have evolved for the veterinary market, specifically robenacoxib, a new entrant into the market in 2009 (King et al, 2009; Giraudel et al, 2009; Jung et al, 2009; Schmid et al, 2010), which is the active ingredient in Onsior, marketed by Novartis. NSAID development: COX-1: COX-2 ratios The discovery in 1991 that there are two isoforms of COX, now designated as COX-1 and COX-2 (Xie et al, 1991), was heralded as a major pharmacological advance, with positive therapeutic benefit in relation to NSAID safety. COX-1 was recognised as a constitutive enzyme, present at basal levels in most body cell types. Its roles include platelet aggregation in blood clotting, gastroprotection and, at least partially, renoprotection. The potential side effects of COX-1 inhibition, therefore, include failure to control haemorrhage, perforation, ulceration and bleeding of the gastrointestinal tract, and acute renotoxicity. COX-2 was initially classified as an inducible isoform, synthesised in response to tissue damage 1 / 5

2 both at the site of damage and in the central nervous system. Development of selective COX-2 inhibitors was logical, on the grounds they would retain (but not necessarily improve) therapeutic effects of non-selective inhibitors and decrease classic side effects of non-selective NSAIDs ( Figure 1 ). A potency ratio of 30: 1 or greater will normally ensure that COX-1 inhibition is slight to moderate and of short duration with clinically recommended doses. However, it is now recognised that COX-2 is also a constitutive enzyme in kidneys, eyes, central nervous system and vascular wall. Consequently, there is a concern that, for example, renotoxicity of all NSAIDs, including the coxibs, may be partly due to COX-2 inhibition. It has also been shown experimentally that COX-2 generates not only pro-inflammatory mediators, such as prostaglandin E2 (PGE2), in the early stages of acute inflammation, but also anti-inflammatory prostaglandins in the later stage of tissue repair. The introduction of preferential or selective COX-2 inhibitors into canine medicine has largely achieved the objectives of retained efficacy and some aspects of reduced toxicity. However, the question is whether other properties exist that, in addition to the COX-2 selectivity of coxibs, may improve the safety profile. Pharmacokinetics of NSAIDS When NSAIDs are administered orally or parenterally, the circulatory system delivers the drug to the biophase, that is, the site of action. A successful clinical response is achieved if effective concentrations are attained for most of the inter-dose interval. The concern, however, is that many NSAIDs, both nonselective and COX-2 selective, are delivered to all organs and tissues, not just those targeted for therapy, and this can lead to continuous exposure of noninflamed organs and tissues. NSAID accumulation at peripheral sites of tissue damage The propensity to accumulate preferentially at sites of tissue damage has been demonstrated by some NSAIDs that are nonselective in their COX inhibitory actions, and for one of the newer coxibs, robenacoxib, licensed for use in canine and feline medicine. NSAIDs accumulating in inflamed tissue have in common the properties outlined by Lees et al (2004); Brune and Furst (2007; see Table 1 ). These are compatible with retention of efficacy and the potential for an improved safety profile of tissuetargeting NSAIDs. A high degree (greater than 98 per cent) of binding to plasma protein. A high degree of binding to plasma protein generally limits the extravascular distribution of some, but not all, NSAIDs to most tissues; volumes of distribution are small. However, when tissues are 2 / 5

3 damaged, the permeability of capillaries is markedly increased and plasma containing protein (with attached NSAID) leaks into the interstitial space to cause the characteristic pitting oedema of acute inflammation. Short half-life. A relatively rapid decrease in plasma concentration (as indicated by terminal half-life or mean residence time in the body) reduces the duration of exposure of the body s well-perfused organs (heart, liver and kidney) to high concentrations of the drug within the inter-dose interval. A carboxylic or enolic acid grouping in the molecule. NSAIDs carrying either an enolic or carboxylic acid group are mildly acidic, as are the exudates at the sites of inflammation (Guthrie et al, 1994; Brune and Furst, 2007). Other coxibs in veterinary use are not weak acids. Significantly higher total concentrations in exudate than in transudate and slow rate of elimination from inflammatory exudate. Through the above mechanisms, Lees at al (2004) and Brune and Furst (2007) predicted the achievement of persistent concentrations in inflammatory exudate for weak acid NSAIDs with short plasma halflives, which was confirmed by experimental data. Tissue selectivity of robenacoxib As shown in Table 1, robenacoxib possesses all the above properties required for tissue selectivity (accumulation at a site of inflammation). This quality has been proven in feline studies by Pelligand et al (2011; see Figure 2 ). The slow clearance from exudate explains its long duration of action in inhibiting the synthesis of PGE2, a key mediator of pain in osteoarthritis (OA; King et al 2009; Pelligand et al, 2011). A further study, by Silber et al (2010), compared the penetration of robenacoxib into inflamed versus non-inflamed stifle joints in beagles. The residence time of robenacoxib was similar in both blood and normal joints, but greater in the inflamed stifle. At 10 hours, concentrations in synovial fluid were approximately three-fold higher in the inflamed stifle than in the blood and normal joint. The study also concluded that the rate of entry of robenacoxib into canine synovial fluid was 1.8 times faster in clinical subjects with osteoarthritic joints compared to healthy joints. A final consideration in relation to tissue selectivity is the time course of binding and de-binding of robenacoxib to COX isoforms. Robenacoxib de-binding is virtually instantaneous from COX-1, whereas it forms a slowly reversible complex with COX-2; the half-life for dissociation from COX-2 is approximately 25 minutes (King et al, 2009). 3 / 5

4 Implications of tissue selectivity Rapid clearance from blood considerably reduces the duration of exposure of the pharmacokinetic central compartment, which includes the well-perfused organs (kidney, liver, heart and blood vessels), to high robenacoxib concentrations. At the same time, robenacoxib is cleared much more slowly from sites of inflammation and synovial fluid in dogs with OA. These observations, together with high selectivity for COX-2, account for the safety profile of robenacoxib in dogs and cats. References Brune K and Furst D E (2007). Combining enzyme specificity and tissue selectivity of cyclooxygenase inhibitors: towards better tolerability?, Rheumatology 46: Giraudel J M, Toutain P L, King J N and Lees P (2009). Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib, Journal of Veterinary Pharmacology and Therapeutics 32: Guthrie A J, Short C R, Swan G E, Mulders M S G, Killeen V M and Nurton J P (1994). Proceedings of the 6th International Congress of the European Association for Veterinary Pharmacology and Toxicology, Blackwell Scientific Publications, Oxford, UK: Jung M, Lees P, Seewald W and King J N (2009). Analytical determination and pharmacokinetics of robenacoxib in the dog, Journal of Veterinary Pharmacology and Therapeutics 32: King J N, Dawson J, Esser R E, Fujimoto R, Kimble E F, Maniara W, Marshall, P J, O Byrne L, Quadros E, Toutain P L and Lees P (2009). Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2, Journal of Veterinary Pharmacology and Therapeutics, 32: King J N, Rudaz C, Borer L, Jung M, Seewald W and Lees P (2010). In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: a comparative study, Research in Veterinary Science 88: Lees P, Landoni M F, Giraudel J and Toutain P L (2004). Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest, Journal of Veterinary Pharmacology and Therapeutics 27: Pelligand L, King J N, Toutain P L, Elliott J and Lees P (2011). PK-PD modelling of robenacoxib in a feline tissue cage model of inflammation, Journal of Veterinary Pharmacology and Therapeuticsin press. Schmid V B, Seewald W, Lees P and King J N (2010). In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study, Journal of Veterinary Pharmacology and Therapeutics 33: Silber H E, Burgener C, Letellier M, Peyrou M, Jung M, King J N, Gruet P and Giraudel J M (2010). Population pharmacokinetic analysis of blood and joint synovial fluid concentrations of robenacoxib from healthy dogs and dogs with osteoarthritis, Pharmaceutical Research 27: 2,633-2,645. Xie W L, Chipman J G, Robertson D S, Erikson R L and Simmons D L (1991). Expression of a mitogenresponsive gene encoding prostaglandin synthase is regulated by mrna 4 / 5

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