Source: European Medicines Agency (EU) Publisher: Glenmark Pharmaceuticals s.r.o., Hvězdova 1716/2b, 140 78, Praha 4, Czech Republic
Pharmacotherapeutic group: Platelet aggregation inhibitors, excluding heparin. Antithrombotic agents
ATC code: B01AC18
Triflusal reduces thromboxan biosynthesis through irreversible inhibition of platelet cyclooxygenase, sparing prostacyclin biosynthesis because its effect on vascular cyclooxygenase at therapeutic doses is negligible. On the other hand, the main triflusal metabolite, 2-hydroxy-4-(trifluoromethyl)benzoic acid (HTB), is a reversible platelet cyclooxygenase inhibitor and, because of its long elimination half-life (approximately 34 h), contributes to the antiplatelet activity of triflusal. Both triflusal and HTB are able to increase the concentration of cyclic adenosine 5-monophosphate (cAMP) in platelets through inhibition of platelet phosphodiesterases. In addition, triflusal has been shown to stimulate in vitro and ex vivo nitric oxide release in human neutrophils, which also contributes to the antiplatelet effect.
Triflusal has been shown to inhibit platelet aggregation in both healthy volunteers and patients. In ex vivo studies, triflusal inhibited by 65% the platelet aggregation induced by arachidonic acid in platelet-rich plasma (PRP) from healthy volunteers 24 hours after administration of a single 600 mg dose. Repeated triflusal administration (600 mg/day for 7 days) caused a 50%-75% inhibition of platelet aggregation (PRP) induced by arachidonic acid, ADP (adenosine diphosphate), epinephrine, or collagen.
In a randomised, multicentre, double-blind, placebo-controlled clinical trial on 122 patients of both sexes aged 40-75 years with Lériche-Fontaine stage II chronic obliterating peripheral arteriopathy, of whom 59 received triflusal (600 mg/day) and 63 placebo for a period of 6 months, rates of success (defined as a 40% increase in the total distance walked compared to baseline) were 63.6% with triflusal versus 22.5% with placebo (p=0.0001). An analysis of the total distance walked without experiencing pain as compared to baseline showed triflusal to be superior to placebo, but the difference was not statistically significant (p=0.05). On the other hand, significant differences favouring triflusal (p=0.003) were seen in improvement of symptoms related to vascular disease (limb paraesthesia, heaviness, and coldness).
In a randomised, double-blind clinical trial involving 2270 patients with acute myocardial infarction treated for 35 days with triflusal (600 mg once daily) or ASA (300 mg once daily) (TIM Study), incidence rates of gastrointestinal bleeding were 0.9% for triflusal versus 1.5% for ASA, and intracranial haemorrhage rates were 0.3% for triflusal versus 1% for ASA. In both groups, most of those haemorrhages were seen in patients who received concomitant treatment with thrombolytic agents and heparin. In another randomised, double-blind clinical trial involving 2107 patients with stroke treated for a mean of 30 months with triflusal (600 mg once daily) or ASA (325 mg once daily) (TACIP Study), the incidence of clinically relevant bleeding was significantly lower (p=0.004) in patients treated with triflusal (1.9% vs 4.0%).
Triflusal is rapidly absorbed (t1/2 Ka = 0.44 h), and has an absolute bioavailability of 83%-100%. Triflusal is rapidly metabolised by the action of esterases to its main metabolite, HTB, which is also active. In urine, a secondary metabolite was identified as a HTB-glycine conjugate. Plasma half-life (t1/2) was 0.53 ± 0.12 h for triflusal and 34.3 ± 5.3 h for HTB. Elimination preferentially occurs through renal excretion (renal clearance >60% at 48 hours). Unchanged triflusal, HTB, and the HTB-glycine conjugate were detected in urine.
Following administration of a single oral dose of triflusal 300 mg or 900 mg to healthy volunteers, mean triflusal peak plasma concentrations (Cmax) were 3.2 ± 1.9 μg/mL and 11.6 ± 1.7 μg/mL respectively, while the Cmax for HTB reached 36.4 ± 6.1 μg/mL and 92.7 ± 17.1 μg/mL. Time to Cmax (tmax) was 0.88 ± 0.26 h for triflusal and 4.96 ± 1.37 h for HTB at the 900 mg dose. HTB pharmacokinetic parameters after repeated administration (triflusal 300 mg three times daily or 600 mg once daily for 13 days) showed steady state peak plasma concentrations (Cmaxss) of HTB of 178 ± 42 μg/mL and 153 ± 37 μg/mL respectively.
At therapeutic concentrations, HTB has a plasma albumin binding rate of 98%-99%. This binding was not significantly altered by the presence of caffeine, theophylline, glisentide, enalapril, cimetidine, or warfarin. However, HTB free fraction significantly increased in the presence of non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, ibuprofen, indomethacin, naproxen, piroxicam. or salicylic acid. At high concentrations, HTB displaced NSAIDs, glisentide, and warfarin from their protein binding sites. These agents have affinity for the same albumin binding sites and may displace each other as a function of their affinities for the protein and the total concentration of the displacing agent.
In elderly volunteers, steady state plasma concentrations of triflusal and HTB were reached 3 to 5 days after administration of triflusal 300 mg twice daily. Values of AUCss, Cmax, and tmax in elderly volunteers were not significantly different from those reported in young volunteers. Plasma half-lives (t1/2) were 0.92 ± 0.16 h for triflusal and 64.6 ± 6.6 h for HTB. However, this increase has no clinical relevance warranting dose adjustment in elderly subjects.
In patients with end-stage chronic renal disease on conventional haemodialysis, HTB plasma concentrations measured before and after dialysis were similar.
Preclinical data revealed no special risk for humans, according to the results of conventional safety pharmacology, repeated administration toxicity, genotoxicity, and reproductive toxicity studies.
After long-term administration of triflusal to rats and dogs (10, 25, and 50 mg/kg/day for 12 months), biochemical, morphological, and histopathological changes were only found at the high dose. The most significant pathological signs were gastrointestinal intolerance, including gastric ulcers, moderate anaemia, vomiting (in dogs), slight changes in organ weight (liver, kidneys, heart, and spleen), and mild to moderate nephrosclerosis. Most of these effects, except for nephrosclerosis, were reversible 13 weeks after treatment discontinuation.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
