The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trials

Abstract

Summary. Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min ). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h )1 , 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux -rapid onset of action and long-acting anticoagulant effect -offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.

Biochemical and Biological Characterization of a New Oxidized Avidin with Enhanced Tissue Binding Properties

“…These (strept)avidin-biotin techniques are also found to be useful in medical applications in vivo to localize and image cancer cells and to pretarget drugs to tumors (3)(4)(5)(6). In addition, the use of avidin to neutralize the anticoagulant activity of idrabiotaprinux by increasing the plasma clearance of the idrabiotaprinux-avidin complex has been demonstrated (7).…”

“…Chicken avidin and bacterial streptavidin are tetrameric proteins containing four identical subunits (homotetramer), each of which can bind to biotin (vitamin B 7 and vitamin H) with a high degree of affinity and specificity. The dissociation constant of the (strept)avidin-biotin system is measured to be K D ϭ Ϸ10 Ϫ15 M, making it one of the strongest known noncovalent bonds (1).…”

Current approaches in atrial fibrillation treatment

“…AME-DEUS çalışmasına 4576 hasta alınmış olup inme ve emboli oranı warfarinde %1.3 idraparinux'ta %0.9 bulunmuştur (p=0.0007). Kanama oranları warfarine göre fazla olması nedeniyle %19.7 vs %11.3 (p=0.0001) nötralize edilebilen formu biotinylated idraparinux üretilmiştir ve en son hasta alımı Eylül 2010 olan BOREALİS-AF çalışmasında warfarin ile karşılaştırılmaktadır [40,41]. Direk FXa inhibitörle-rinden rivoraxaban 1100 merkezde 14.000 den fazla hasta alınan ROCKET-AF çalışmasında nonvalvu-ler AF'de tek doz kullanımı warfarinle karşılaştırıl-mış olup non inferior bulunmuştur [42].…”

New Prospective for the Management of Low-Risk Pulmonary Embolism: Prognostic Assessment, Early Discharge, and Single-Drug Therapy with New Oral Anticoagulants

“…It requires only a single weekly subcutaneous injection to obtain its antithrombotic effect [161–163]. …”

“…A biotin moiety was added to idraparinux to create idrabiotaparinux, a molecule with the possibility to rapidly reverse its anticoagulant activity by infusing avidin [161, 165, 166]. …”