Background

Firocoxib (FX; Figure 1) is a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 (COX-2) mediated prostaglandin synthesis. Firocoxib is a new generation of anti-inflammatory and analgesic drugs. Osteoarthritis (OA) is a common cause of lameness in horses, with the annual national (US) cost of lameness to horse owners estimated to be in the billions of dollars. OA, also known as degenerative joint disease, is defined by a group of disorders characterized by articular cartilage deterioration accompanied by changes in the bone and soft tissues of the joint. Firocoxib is approved for the control of pain and inflammation associated with OA for up to 14 days. Firocoxib in a paste form (also available in injectable form) has become a commonly prescribed treatment of clinicians for long-term treatment of OA, and more specifically chronic OA.The original manufacturer is the French company Melia, which is used to treat pain and inflammation associated with osteoarthritis in dogs, the selectivity of firocoxib for COX-2 is about 380 times that of COX-1. It currently approved for veterinary use in dogs and horses under the brand names Equioxx and Previcox. Firocoxib is not intended or approved for use in human medicine.[1]

Description and physicochemical properties

The IUPAC name of firocoxib is 3-(cyclopropylmethoxy)?5,5-dimethyl-4-(4-methylsulfonylphenyl)furan-2-one. Firocoxib is practically insoluble in water(0.0105 mg/mL), soluble in ethanol (3 mg/mL), and highly soluble indimethyl sulfoxide (67 mg/mL). The chemical properties are listed in Table 1.[2]

Synthesis of Firocoxib

In this paper, the synthetic route of Firocoxib is studied, the synthetic route is investigated and optimized (Figure 2), and the optimized synthetic process is determined: the key carboxylic acid intermediate 2-(cyclopropylmethoxy)acetic acid was obtained by nucleophilic substitution reaction (sodium 2-chloroacetate: cyclopropylmethanol:t-BuOK=1:2:2) with sodium 2- chloroacetate and cyclopropylmethanol as raw materials. The intermediate 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one was prepared from cheap and readily available methyl(phenyl)sulfane and isobutyryl chloride by Friedel Crafts reaction (methyl(phenyl)sulfane: isobutyryl chloride:ACl3=1:1.3:1.3), bromination (2-methyl-1-(4- (methylthio)phenyl)propan-1-one:HBr:DMSO=1:1.1:1.1), hydrolysis (2-bromo-2-methyl-1-(4-(methylthio)phenyl)propan-1-one:NaOH=1:1.4) and oxidation (2-hydroxy-2-methyl-1-(4-(methylthio)phenyl)propan-1-one:Oxone=1:1.4). The intermediate 2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one and intermediate 2-(cyclopropylmethoxy)acetic acid were esterified (2-hydroxy-2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one:2- (cyclopropylmethoxy)acetic acid:SOCl₂:DMF:DMAP:triethylamine=1:2:2:0.15:0.3:4) and ring-closed (2-methyl-1-(4-(methylsulfonyl)phenyl)-1-oxopropan-2-yl-2-(cyclopropylmethoxy)acetate:isopropyl trifluoroacetate:DBU=1:1.4:1.8) to obtain the target product Firocoxib, and scaled up to the kilogram level, the total yield is 43%. Firocoxib was confirmed by LC-MS, H-NMR and C-NMR, and the purity was 99.83% determined by HPLC. The process is suitable for industrial scale-up production and is economical and environmentally friendly, and achieves high-efficiency and green industrial manufacturing of Firocoxib.[3]

Pharmacology overview

Firocoxib presents remarkable pharmacokinetics and pharmacodynamics compared to other coxibs. It has an oral bioavailability of 80% or higher and is effectively absorbed by horses. Its volume of distribution is around 2L/kg, and it is slowly eliminated. Due to the long elimination half-life (around 2 days), which allows a once daily dosing, a single 0.3 mg/kg loading dose has been recommended. This enables the establishment of steady-state drug concentrations within 24 h, making it appropriate for acute treatment as well. Its IC₈₀ is equal to 103 ng/mL in whole blood and, with an EC₅₀ of 27 ng/mL, it has the highest affinity for its receptor compared to the other commonly administered NSAIDs in horses.[2]

Safety evaluation

When taken alone at the prescribed dose (0.1 mg/kg for up to 42 days), there has been a very low rate of documented side effects for oral and IV administration of firocoxib . When given oral paste firocoxib at the prescribed dose, four of 476 (0.9%) horses experienced lip edema,brief episodes of colic, mild oral ulcerations, lethargy, and sedation, and one of 48 (2%) horses experienced labial and tongue edema and hypersalivation. Six horses were given firocoxib (0.1 mg/kg)and phenylbutazone (4.4 mg/kg) for ten days and their creatinine and total protein levels increased, indicating renal impairment. Besides this study, no side effects in horses were noted in the previously performed pharmacokinetic studies.

Target animal-safety studies revealed oral ulceration in horses given firocoxib oral paste at three and five times the recommended dose for 42 days,as well as clinical chemistry and coagulation disturbances in horses given five times the recommended dose for 42 days. In a subsequent research, all horses had delayed healing of preexisting oral ulcers, and one of eight horses developed renal papillary necrosis, when administered firocoxib paste at the recommended dose. In horses given one to five times the approved dose of firocoxib, IV administration has been linked to injection-site edema and perivascular inflammation.

As firocoxib can be used as a palliative for multiple pathologiesand inflammatory processes for its proven safety, it can cause indiscriminate use and even more in sport horses that are exposed to joint diseases. This is why it is important to take in account drug use regulation, so that these concentrations do not exceed their limits that could harm the animal not only in adverse effects of the drug (which are usually few) but also when affected sport horses are forced to compete they are exposed to develop more serious pathologies than those presented previously.[4]

To summarize, when used at the recommended doses, firocoxib has relatively few side effects. With no reports of gastric ulceration as an adverse effect after prolonged administration, there is a widespread clinical view that firocoxib is definitely a safe option to non-preferential NSAIDs, particularly in horses with gastrointestinal ulceration. [2]

Conclusion

In vitro and in vivo studies have demonstrated that firocoxib is a highly selective COX-2 inhibitor. Both an injectable formulation for intravenous administration at a dose of 0.09 mg/kg for five days and an oral paste formulation with a dose of 0.1 mg/kg for 14 days are approved for use in treating OA in horses. A canine tablet formulation is also available, and may be an equally effective anti-inflammatory drug compared to the other formulations. However, the use of the canine formulation iscontroversial because it is unapproved, yet it is often provided because it is less expensive than the paste. Firocoxib is well absorbed in horses, with an oral bioavailability of 80% or more. It is slowly eliminated, and Vd values are around 2 L/kg. Because of the long elimination half-life,which has been reported to be as long as two days, it may take several days to achieve steady concentrations and maximal efficacy. To remedy this, a single 0.3 mg/kg loading dose has been recommended, which allows for the establishment of average steady-state drug concentrations within 24 h, making it suitable for acute treatment as well. It should be noted that firocoxib in neonates displays different pharmacokinetics than in adult horses. After 14 days of dosing in clinical trials on horses with spontaneously occurring OA, the overall clinical efficacy of firocoxib was optimal at the recommended doses. 

References

[1]Donnell JR, Frisbie DD. Use of firocoxib for the treatment of equine osteoarthritis. Vet Med (Auckl). 2014;5:159-168. Published 2014 Nov 4. doi:10.2147/VMRR.S70207

[2]Fadel C, Giorgi M. Synopsis of the pharmacokinetics, pharmacodynamics, applications, and safety of firocoxib in horses. Vet Anim Sci. 2023;19:100286. Published 2023 Jan 11. doi:10.1016/j.vas.2023.100286

[3]Li L.Study on the synthesis process of Firocoxib [D].South China University of Technology, 2020. DOI: 10.27151/d.cnki.ghnlu.2020.001902

[4]Rangel-Nava A, Ramírez-Uribe JM, Recillas-Morales S, Ibancovichi-Camarillo JA, Venebra-Mu?oz A, Sánchez-Aparicio P. Pharmacological Regulation in the USA and Pharmacokinetics Parameters of Firocoxib, a Highly Selective Cox-2, by Pain Management in Horses. J Equine Vet Sci. 2019;77:36-42. doi:10.1016/j.jevs.2019.02.007