NON-steroidal anti-inflammatory drugs (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 Veterinary Medicines Directorate (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).
The NSAID development story: COX1:COX2 ratios
The discovery in 1991 that there are two isoforms of COX, now designated 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, on the other hand, was initially classified solely as an inducible isoform, synthesised in response to tissue damage, both at the site of damage and in the central nervous system. The development of selective COX-2 inhibitors was therefore a logical step, on the grounds that they would retain (though not necessarily improve on) the therapeutic effects of nonselective inhibitors, and decrease the classic side-effects of the non-selective NSAIDs (Figure 1).
A potency ratio of 30:1 or greater will normally ensure that COX-1 inhibition is slight/moderate and of short duration with clinically recommended doses. It is now recognised, however, that COX-2 is also a constitutive enzyme in the kidney, eye, CNS and vascular wall. Consequently, there is a concern that renotoxicity (for example) of all NSAIDs, including the coxibs, may be due in part to COX-2 inhibition.
Moreover, it has also been shown experimentally that COX-2 generates not only pro-inflammatory mediators, e.g. 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 now is: are there other properties, in addition to the COX-2 selectivity of coxibs, which 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, and 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 non-selective and COX2 selective, are delivered to all organs and tissues, not just those targeted for therapy, and this can lead to continuous exposure of non-inflamed organs and tissues.
Tissue selectivity: NSAID accumulation at peripheral sites of tissue damage
The propensity of some NSAIDs to accumulate preferentially at sites of tissue damage has been demonstrated by some NSAIDs, non-selective 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) and Brune and Furst (2007) – Table 1; these are compatible with retention of efficacy and the potential for an improved safety profile of tissue targeting NSAIDs.
- A high degree (>98%) 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 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 et al (2004) and Brune and Furst (2007) predicted the achievement of persistent concentrations in inflammatory exudate for weak acid NSAIDs with short plasma half-lives and this was confirmed by experimental data.
Tissue selectivity of robenacoxib
As shown in Table 1, robenacoxib possesses all of the above properties required for tissue selectivity (accumulation at a site of inflammation); this quality has been proven in recent feline studies by Pelligand et al (2011) (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 noninflamed 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 debinding 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 of the order of 25 minutes (King et al, 2009).
Implications of tissue selectivity with robenacoxib
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 the dog and cat. Robenacoxib exemplifies the next generation of NSAIDs for use in companion animal medicine.
References
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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: 444-452.
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 mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing. Proceedings of the National Academy of Sciences of the United States of America 88: 2,692-2 696.
