Effects of a Synthetic Factor Xa Inhibitor (JTV-803) on Various Laboratory Tests

Töbü, Mahmut; Iqbal, Omer; Hoppensteadt, Debra; Shultz, Christopher; Jeske, Walter; Fareed, Jawed

doi:10.1177/107602960200800404

Cited by 16 publications

(13 citation statements)

References 10 publications

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“…The PT assay has been widely used to monitor anticoagulant activity of warfarin (Kimmel 2008). However, it has been shown that PT is not a sensitive assay for Xa inhibition (Tobu et al 2002;Walenga and Hoppensteadt 2004;Paccaly et al 2006). The commercially available HCT employs exogenous bovine fXa as the activator.…”

Section: Discussionmentioning

confidence: 99%

Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

Luettgen

Zhang

et al. 2011

Eur J Drug Metab Pharmacokinet

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Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10-30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST(®) clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E (max) model for anti-fXa assay and a linear model for PT and HCT assays. The IC(50) values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K ( i ) values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K ( i ) for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.

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Section: Discussionmentioning

confidence: 99%

Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

Luettgen

Zhang

et al. 2011

Eur J Drug Metab Pharmacokinet

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“…The HEMOCLOT assay is provided with dabigatran calibrators and yields a linear relationship (R = 0.99) with dabigatran concentrations from approximately 50 to 2000 ng mL )1 [20]. As the TT and dTT assays measure thrombin activity downstream from FXa, they are insensitive to the effects of FXa inhibitors [21]. Thus, although excessive concentrations of any of the new oral agents can prolong both the PT and APTT, the TT may help to identify which of the new anticoagulants is present; in the absence of confounding effects from multiple anticoagulants, a prolonged TT indicates dabigatran, whereas a normal TT is indicative of an FXa inhibitor.…”

Section: Dabigatranmentioning

confidence: 99%

Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants

García

Barrett

Ramacciotti

et al. 2013

Journal of Thrombosis and Haemostasis

111

119

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Summary. In contrast to vitamin K antagonists, which reduce the functional levels of several coagulation factors, the new oral anticoagulants specifically target either thrombin or factor Xa. These new agents have such predictable pharmacokinetics and pharmacodynamics that routine coagulation monitoring is unnecessary. However, there are still some situations in which measurement of anticoagulant effect may be required. The coagulation assays that are used to monitor heparin derivatives or vitamin K antagonists may not always accurately reflect the anticoagulant activity of the new oral anticoagulants, and specialized assays may be needed. In this article, we: (i) identify situations in which assessment of anticoagulant effect may aid treatment decisions; (ii) describe the effects of the new oral anticoagulants on the various coagulation tests; (iii) review the specialized coagulation assays that have been developed to measure the anticoagulant effects of the new oral anticoagulants; and (iv) provide a clinical perspective on the role of coagulation testing in the clinical management of patients treated with the new oral anticoagulants.

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“…17 It is partly attributable to the difference of assay reagents. 18,19 Administration of darexaban (60-240 mg qd) resulted in dose-dependent decreases in F 1þ2 levels, in contrast to no effect in the placebo group. This demonstrates that F 1þ2 can be used as a biomarker of darexaban's anticoagulant effect in future pivotal studies.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Darexaban, an Oral Direct Factor Xa Inhibitor, in Healthy Elderly Japanese Subjects

Kadokura

Oikawa

Miyata

et al. 2013

Clinical Pharm in Drug Dev

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The clinical pharmacokinetics, pharmacodynamics, safety and tolerability of darexaban after single and multiple once-daily doses of 60, 120, and 240 mg in healthy elderly Japanese subjects were assessed. Following oral administration, darexaban was rapidly and extensively metabolized to darexaban glucuronide, which is an active glucuronide metabolite. Plasma concentrations of darexaban glucuronide increased with dose, and Cmax and AUC increased dose-dependently after both single and repeated doses. Cumulative urinary excretion of darexaban glucuronide up to 24 hours after repeated doses ranged from 28.59% to 36.50%. PT-INR, aPTT, and FXa activity were prolonged or decreased dose-dependently after both single and repeated doses of darexaban. The time-profile of pharamcodynamic parameters closely followed the time-concentration profile of darexaban glucuronide. Five adverse events occurred in the present study (4: darexaban [16.7%]; 1: placebo [8.3%]), all of which were mild in severity and required no treatment.

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Effects of a Synthetic Factor Xa Inhibitor (JTV-803) on Various Laboratory Tests

Cited by 16 publications

References 10 publications

Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor

Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants

Clinical Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Darexaban, an Oral Direct Factor Xa Inhibitor, in Healthy Elderly Japanese Subjects

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