A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays

Carlsson, Stefan; Mattsson, Christer; Eriksson, Ulf G.; Sarich, Troy C.; Wåhlander, Karin; Eliasson, Åsa; Karlson, Björn W.; Sheth, Sunita; Held, Peter

doi:10.1016/j.thromres.2004.07.001

Cited by 33 publications

(40 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the PT-INR is no suitable predictor of BIBT 986 BS concentrations. In contrast, the linear correlation of plasma concentration to APTT within the dose range tested differentiates BIBT 986 from pure direct thrombin inhibitors, which have curvilinear relationship in a therapeutic dose range [5,11,13,14].…”

Section: Pdmentioning

confidence: 77%

“…In Study 1, blood samples for coagulation tests were taken at all, but the 36-h time points as already described for PK. In Study 2, they were taken at: predose ()1 h), 24, 31.98, 32.5, 33, 34, 36, 44, and 56 h after start of infusion; and Study 3 at: predose ()1 h), 2,3,4,5,6,8,12, and 24 h after start of infusion.…”

Section: Pharmacodynamic Parametersmentioning

confidence: 99%

“…Dabigatran, an oral direct thrombin inhibitor, has proven its safety and efficacy in clinical studies and is now undergoing extensive clinical evaluation [5][6][7]. In contrast to these compounds, BIBT 986, a novel synthetic, small molecule (MW of the HCL salt: 542 Da), is a specific, direct, competitive and reversible inhibitor of both, FXa (K i 26 nM) and thrombin, with a slightly higher inhibitory effect on thrombin (K i 2.7 nM).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

Graefe-Mody

Schühly

Rathgen

et al. 2006

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Summary. Background: Current anticoagulant development focuses on agents with predictable pharmacokinetic and pharmacodynamic (PD) properties. BIBT 986 is a novel potent anticoagulant with a dual mechanism of action: it competitively inhibits factor (F) Xa and FIIa. Aims: To determine the safety, tolerability, pharmacokinetics (PK) and PD of BIBT 986 following intravenous infusion in healthy male volunteers. Methods: In three randomized, doubleblind, placebo-controlled trials, subjects were administered by intravenous infusion escalating doses of BIBT 986 for up to 32 h. BIBT 986 concentrations were determined in plasma and urine samples by high pressure liquid chromatography tandem mass spectrometry. Pharmacodynamic response was assessed by measuring the changes in blood coagulation times. Activated partial thromboplastin time, International Normalized Ratio, thrombin time and ecarin clotting time were determined and compared with baseline results. Results: In all three studies, intravenous infusion of BIBT 986 was safe and well tolerated. BIBT 986 exhibited linear PK over the dose range tested. Clearance was about 8 L h)1 and V ss about 50 L. Apparent steady state concentrations were reached within 24 h, indicating a dominant half-life of about 6 h. The terminal half-life of BIBT 986 was approximately 12 h. Renal excretion contributes approximately 50% to total elimination. Overall interindividual variability in pharmacokinetic and PD parameters was < 40%. There was a linear correlation between plasma concentrations and PD responses, suggesting excellent predictability. Conclusion: BIBT 986 is the first small molecule of a novel class of anticoagulants that potently and directly inhibits both coagulation FXa and thrombin. It has predictable pharmacokinetic and PD characteristics.

show abstract

Section: Pdmentioning

confidence: 77%

Section: Pharmacodynamic Parametersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

Graefe-Mody

Schühly

Rathgen

et al. 2006

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

show abstract

“…PT is a measure of the activity of the vitamin K dependent factors II, VII, IX and X and also of factor V, which is not vitamin K dependent. Although its use to measure the anticoagulant effect of warfarin in patients in a concentration-dependent manner is well established, it has been reported to have low sensitivity to therapeutic plasma melagatran concentrations in patients [13]. APTT is prolonged when any of the factors VIII, IX and X in the intrinsic system are inhibited such as by DTIs and warfarin.…”

Section: Haematological Measurementsmentioning

confidence: 99%

“…APTT is prolonged when any of the factors VIII, IX and X in the intrinsic system are inhibited such as by DTIs and warfarin. ECT is prolonged when thrombin is inhibited and can provide a measure of the effect of ximelagatran [13] but not warfarin.…”

Section: Haematological Measurementsmentioning

confidence: 99%

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

2008

View full text Add to dashboard Cite

Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation

Soslau

Ando

Floyd

et al. 2007

J Thromb Thrombolysis

View full text Add to dashboard Cite

These results indicate that melagatran acts as both a direct thrombin inhibitor and indirectly by some interaction with the platelet membrane. While melagatran has been withdrawn from clinical use, its ability to differentially inhibit gamma-thrombin/PAR-4 versus alpha-thrombin/PAR-1 at low doses may warrant it, or less toxic analogs to be used in the future for as yet unknown disease states involving PAR-4.

show abstract

A review of the effects of the oral direct thrombin inhibitor ximelagatran on coagulation assays

Cited by 33 publications

References 55 publications

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

Pharmacokinetics and pharmacodynamics of BIBT 986, a novel small molecule dual inhibitor of thrombin and factor Xa

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

Effect of low and high dose melagatran and other antithrombotic drugs on platelet aggregation

Contact Info

Product

Resources

About