Indobufen:Pharmacodynamic and Pharmacokinetic Properties and its Efficacy Comparison with Aspirin

Introduction

Indobufen, (±)-2-[p-(1-oxo-2-isoindolinyl)phenyl]butyric acid, is an orally active antiplatelet agent which inhibits platelet activation,adhesion and aggregation. These platelet functions are essentially suppressed through the reversible inhibition of arachidonic acid metabolism at the level of platelet cyclo-oxygenase (fig. 1). In contrast to the effects of aspirin (acetylsalicylic acid),which irreversibly acetylates cyclo-oxygenase, the antiplatelet effects of indobufen are short-lived and normal platelet function resumes within 24 hours after cessation of indobufen administration. Indobufen thus has a reduced risk of the prolonged bleeding time, generally associated with antiplatelet treatment.[1] Improvements in walking distances and microcirculatory parameters have been achieved during therapy with indobufen in patients with peripheral vascular disease and intermittent claudication. Indobufen has been shown to be as effective as aspirin plus dipyridamole in preventing the reocclusion of coronary and femoro-popliteal artery bypass grafts and has been shown to significantly reduce platelet deposition on haemodialysis membranes. Initial studies have also indicated that indobufen may have a prophylactic effect on the incidence of secondary thrombotic events following transient ischaemic attack or mild stroke and may be effective in the prophylaxis of migraine. Indobufen is well tolerated following oral administration and has been associated with a low incidence of adverse effects rarely requiring withdrawal of treatment.Thus, available evidence indicates that indobufen may be an effective alternative to aspirin for the treatment of cerebral, peripheral and coronary vascular diseases with the advantage of a lower incidence of gastrointestinal effects compared to high dose aspirin, rendering indobufen more suitable for longer term therapy. [2]

Pharmacodynamic Properties

Indobufen is an isoindolinyl phenyl-butyric acid derivative that produces reversible inhibition of platelet aggregation in vitro and ex vivo. Platelet cyclo-oxygenase is reversibly inhibited by indobufen and this results in decreased production of thromboxane B2, a potent activator of platelet aggregation. The drug inhibits the second wave of aggregation induced by adenosinediphosphate (ADP), epinephrine (adrenaline) and platelet activating factor (PAF) in platelets from healthy volunteers and from patients with occlusive vascular disease, and has a dose-dependent inhibitory effect on collagen- and arachidonic acid-induced aggregation. A maximal inhibitory effect on agonist-induced platelet aggregation is observed 2 hours after a single oral dose of indobufen 200mg. This inhibition is still significant (90%) after 12 hours and is reversible within24 hours. Indobufen therapy (200mg twice daily) significantly inhibits spontaneous platelet aggregation ex vivo compared with placebo in platelets from atherosclerotic patients, and this is evident 2 to 8 hours after administration.Other effects include a reduction in the platelet levels of adenosine triphosphate (ATP), serotonin (5-hydroxytryptamine), platelet factor 3 (PF3), PF4 and J3-thromboglobulin (BTG), decreased platelet adhesiveness in platelets from healthy volunteers and from atherosclerotic patients and an improvement in red blood cell deformability in patients with occlusive vascular disease.Bleeding time is prolonged following indobufen administration, with a maximal effect 2 hours after administration; however, this increase is not clinically relevant and values remain within the upper normal limit at all times.Improvements in microcirculatory parameters, including resting and standing skin blood flow and the venoarteriolar reflex have been found in patients with intermittent claudication and diabetes following indobufen therapy. Indobufen demonstrated antithrombotic activity in vivo in animals against the lethal thrombotic effects of epinephrine and collagen and prevented graft occlusion following vascular surgery. [2]

Pharmacokinetic Properties

Indobufen is rapidly and completely absorbed after oral administration, reaching peak plasma concentrations within 2 hours. The elimination half-life (t1⁄2β) is about 7 hours and the low apparent volume of distribution of 15L is a reflection of the high plasma protein binding (>99%) of the drug. The fraction of the administered dose excreted in urine within 48 hours of administration is about 70to 80%, with most excreted via the kidney as glucuronic acid conjugates and 11to 13% excreted as unchanged drug. Excretion rates are not affected by route of administration (oral or intravenous) and renal clearance is not affected by the presence of food. Dose reductions may be required in the elderly and patients with renal insufficiency, because the clearance of indobufen is significantly prolonged in these populations.Few drug interactions have been reported with indobufen, although an increase in the area under the concentration-time curve (AUC) of glipizide has been documented.[1]

Indobufen versus aspirin in patients with indication for antiplatelet therapy

Aspirin is commonly recommended for individuals who have experienced stroke or myocardial infarction (MI). Indobufen, a cyclooxygenase-1 inhibitor, has been studied as a potential alternative. Researchers conducted a meta-analysis and trial sequential analysis (TSA) to compare indobufen with aspirin in patients requiring antiplatelet therapy.Researchers searched PubMed, Scopus, and Cochrane Central for studies that compared indobufen and aspirin antiplatelet therapies. Researchers focused on efficacy outcomes, such as composite vascular events, MI, and ischemic stroke, and safety outcomes, such as major bleeding and any bleeding. Heterogeneity was assessed using I2 statistics, and our analysis followed the PRISMA guidelines. RESULTS: The review included 5 studies with 11,943 patients (indobufen n = 5952, 49.84 %), three involving post-MI and two involving post-stroke patients. No significant differences were found between the groups in composite vascular events at 90 days (RR 0.84; 95 % CI 0.46-1.53; p = 0.560; I2 = 53 %) and 1-year (RR 1.13; 95 % CI 0.99-1.29; p = 0.08; I2 = 0 %). MI (RR 0.73; 95 % CI 0.43-1.22; p = 0.22; I2 = 0 %), ischemic stroke (RR 1.16; 95 % CI 0.99-1.37; p = 0.06; I2 = 0 %), and cardiovascular death (RR 1.35; 95 % CI 0.80-2.26; p = 0.257; I2 = 0 %) at 1-year also showed no significant differences. Major bleeding at 1 year (RR 0.73; 95 % CI 0.41-1.31; p = 0.297; I2 = 64 %) was comparable, but any bleeding at 1 year showed a significant difference (RR 0.65; 95 % CI 0.43-0.98; p = 0.03; I2 = 87 %) favoring indobufen. Subgroup analysis of RCTs showed marginally significant increased risk regarding ischemic stroke with indobufen (RR 1.18; 95 % CI 1.00-1.39; p = 0.05). CONCLUSION: The efficacy and safety of antiplatelet therapy with indobufen were comparable to those of aspirin alone. Therefore, indobufen can be considered as a suitable alternative for patients who are intolerant or hypersensitive to aspirin. Nevertheless, additional trials involving larger populations are required to establish their clinical applicability.[3]

References

[1] Bhana N, McClellan KJ. Indobufen: an updated review of its use in the management of atherothrombosis. Drugs Aging. 2001;18(5):369-388. doi:10.2165/00002512-200118050-00007

[2] Wiseman LR, Fitton A, Buckley MM. Indobufen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in cerebral, peripheral and coronary vascular disease. Drugs. 1992;44(3):445-464. doi:10.2165/00003495-199244030-00009

[3] Cavalcante DVS, Krishna MM, Joseph M, et al. Indobufen versus aspirin in patients with indication for antiplatelet therapy: A systematic review and meta-analysis. Vascul Pharmacol. 2025;158:107465. doi:10.1016/j.vph.2025.107465

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