Chemical formula: C₂₃H₃₆N₆O₅S Molecular mass: 508.64 g/mol PubChem compound: 92722
Argatroban, a synthetic L-arginine derivative, is a direct thrombin inhibitor (molecular weight 526.65) that binds reversibly to thrombin. Argatroban exerts its anticoagulant effect independently of antithrombin III and inhibits fibrin formation; activation of coagulation factors V, VIII and XIII; activation of protein C; and platelet aggregation.
Argatroban is highly selective for thrombin; inhibitory constant (Ki) values in studies in vitro with synthetic tripeptides ranged from 5 to 39 nM.
Argatroban is capable of inhibiting the action of both free and clot-associated thrombin. It does not interact with heparin-induced antibodies. There was no evidence of formation of antibodies against argatroban in patients who received multiple doses of argatroban.
Steady-state levels of both argatroban and anticoagulant effect are typically attained within 1-3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma argatroban concentrations increase proportionally with dose (for infusion doses up to 40 microgram/kg/min in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 microgram/kg/min, argatroban increases, in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the International Normalized Ratio (INR) and the thrombin time (TT) in healthy volunteers and cardiac patients.
Argatroban distributes mainly in the extra-cellular fluid. The volume of distribution (Vdβ) was 391 ± 155 ml/kg (mean ± SD). Argatroban is 54% bound in human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34% respectively.
The metabolism of argatroban has not yet been fully characterized. The metabolites identified (M-1, M-2, and M-3) are formed by hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of the metabolites is catalysed in vitro by cytochrome P450 enzymes CYP3A4/5, but this is not a major path of elimination in vivo. The primary metabolite (M1) exerts 40-fold weaker antithrombin effect than argatroban. Metabolites M-1, M-2 and M-3 were detected in the urine, and M-1 was detected in plasma and faeces.
There is no interconversion of the 21-® and 21-(S) diastereoisomers. The ratio of diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (±2%).
On termination of the infusion, the concentration of argatroban decreased rapidly. The apparent terminal elimination half life (mean ± SD) is 52 ± 16 min. Clearance (mean ± SD) was 5.2 ± 1.3 ml/kg/min.
Argatroban is excreted mainly in the faeces, presumably through biliary secretion. Following intravenous infusion of 14C-radiolabelled argatroban 21.8 ± 5.8% of the dose was excreted in urine and 65.4 ± 7.1% in the faeces.
Older people: clearance is approximately 15% lower then in younger persons. No age related dose adjustment is necessary.
Renal impairment: compared with patients with normal renal function (creatinine clearance ≥ 80ml/min) who had a terminal half-life of 47±22 min, patients with severely impaired renal function (creatinine clearance ≤ 29ml/min) had only slight prolongation of this value (65±35 min). No initial dose regimen adjustment with respect to renal function is necessary.
Hepatic impairment: in patients with hepatic impairment (Child Pugh score 7 to 11) clearance was 26% of that of healthy volunteers. Initial dose reduction is required in patients with moderate hepatic impairment. Argatroban is contraindicated in patients with severe hepatic impairment.
Paediatric patients: argatroban clearance is decreased in seriously ill paediatric patients. Based on population pharmacokinetic modelling, clearance in paediatric patients (0.17 L/hr/kg) was 50% lower compared to healthy adults (0.31 L/hr/kg). Population pharmacokinetic data also indicate that the infusion rate should be adjusted according to body weight.
Other special populations: Based on population pharmacokinetic modelling, patients with elevated bilirubin (secondary to cardiac complications or hepatic impairment) had, on average, 80% lower clearance (0.03 L/hr/kg) when compared to paediatric patients with normal bilirubin levels.
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity. Toxicity studies with continuous intravenous infusions and reproduction toxicity studies using daily intravenous bolus injections achieved only limited systemic exposure to argatroban (2 times the exposure seen in humans). Although these studies do not suggest any particular risk to humans, their value is limited by the low systemic exposure realised.
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