Influence of Age on the Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor

Johansson, Linda C.; Frison, Lars; Logren, Ulrika; Fager, Gunnar; Gustafsson, David; Eriksson, Ulf G.

doi:10.2165/00003088-200342040-00006

Cited by 109 publications

(82 citation statements)

References 26 publications

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“…No serious adverse events or adverse events of bleeding were reported. Ximelagatran was not associated with any clinically relevant adverse events, a finding that corroborates previous studies showing ximelagatran to be well tolerated in both healthy volunteers and patients across a range of doses (Bredberg et al, 2003;Eriksson et al, 2003a,b,c;Francis et al, 2003;Gustafsson and Elg, 2003;Johansson et al, 2003;Olsson et al, 2003;Schulman et al, 2003;Wallentin et al, 2003;Sarich et al, 2004a,b,c;Teng et al, 2004;Dahl et al, 2005). Erythromycin was associated with gastrointestinal adverse events such as nausea and abdominal pain, a result consistent with previous findings (Blondeau, 2002).…”

Section: Discussionsupporting

confidence: 87%

“…With anticoagulant efficacy comparable to that of warfarin, currently the primary option for oral anticoagulation, ximelagatran differs from warfarin in having a predictable anticoagulant effect on coagulation assays that correlates closely with melagatran plasma concentrations and stable melagatran pharmacokinetics within and between patients, and in lacking the requirement for coagulation monitoring and lacking interactions with food, alcohol, and many commonly used medications (Bredberg et al, 2003;Eriksson et al, 2003c;Gustafsson and Elg, 2003;Johansson et al, 2003;Sarich et al, 2004a,b,c;Teng et al, 2004). On the basis of its efficacy and safety profiles, ximelagatran has been characterized as a possible alternative to warfarin which, although efficacious, is underutilized because of concerns about safety and tolerability (Boos and More, 2004;Donnan et al, 2004;Francis, 2004).…”

mentioning

confidence: 99%

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Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-Glycoprotein-Mediated Excretion

Eriksson

Dorani²,

Karlsson³

et al. 2006

Drug Metab Dispos

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ABSTRACT:A pharmacokinetic interaction between erythromycin and ximelagatran, an oral direct thrombin inhibitor, was demonstrated in this study in healthy volunteers. To investigate possible interaction mechanisms, the effects of erythromycin on active transport mediated by P-glycoprotein (P-gp) in vitro in Caco-2 and P-gp-overexpressing Madin-Darby canine kidney-human multidrug resistance-1 cell preparations and on biliary excretion of melagatran in rats were studied. In healthy volunteers (seven males and nine females; mean age 24 years) receiving a single dose of ximelagatran 36 mg on day 1, erythromycin 500 mg t.i.d. on days 2 to 5, and a single dose of ximelagatran 36 mg plus erythromycin 500 mg on day 6, the least-squares mean estimates (90% confidence intervals) for the ratio of ximelagatran with erythromycin to ximelagatran given alone were 1.82 (1.64-2.01) for the area under the concentration-time curve and 1.74 (1.52-2.00) for the maximum plasma concentration of melagatran, the active form of ximelagatran. Neither the slope nor the intercept of the melagatran plasma concentration-effect relationship for activated partial thromboplastin time statistically significantly differed as a function of whether or not erythromycin was administered with ximelagatran. Ximelagatran was well tolerated regardless of whether it was administered with erythromycin. Erythromycin inhibited P-gp-mediated transport of both ximelagatran and melagatran in vitro and decreased the biliary excretion of melagatran in the rat. These results indicate that the mechanism of the pharmacokinetic interaction between oral ximelagatran and erythromycin may involve inhibition of transport proteins, possibly P-gp, resulting in decreased melagatran biliary excretion and increased bioavailability of melagatran.Ximelagatran is an oral direct thrombin inhibitor (oral DTI) which is available for the prevention of venous thromboembolic events in patients undergoing elective hip or knee replacement surgery and is being developed for the treatment of venous thromboembolic events, stroke prevention in patients with atrial fibrillation, and the secondary prevention of cardiovascular events after myocardial infarction (Bergsrud and Gandhi,

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Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-Glycoprotein-Mediated Excretion

Eriksson

Dorani²,

Karlsson³

et al. 2006

Drug Metab Dispos

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“…Ximelagatran produces a predictable anticoagulant response after oral administration and no coagulation monitoring appears to be necessary. Because melagatran, the active agent, is eliminated via the kidneys, however, dose adjustments may be needed in patients with severe renal insufficiency (Eriksson et al, 2003e;Johansson et al, 2003). As with other direct thrombin inhibitors, there is no antidote for ximelagatran (Woltz et al, 2004).…”

Section: Ximelagatranmentioning

confidence: 99%

The status of new anticoagulants

Bates¹,

Weitz

2006

Br J Haematol

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SummaryCurrently available anticoagulants include heparin, lowmolecular weight heparin, fondaparinux and warfarin. Despite advances with low-molecular weight heparin and fondaparinux, the currently available agents have limitations that have provided the impetus for the development of new drugs for prevention and treatment of both venous and arterial thromboembolism. Novel anticoagulants targeting specific steps in coagulation are in various stages of development. This paper reviews the pharmacology of these new agents and describes the results of clinical trials with new anticoagulants in more advanced stages of clinical testing.

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“…The half-life of melagatran is slightly prolonged in the elderly, likely reflecting their reduced creatinine clearance. 38 Coagulation monitoring is unnecessary for ximelagatran because it produces a predictable anticoagulant response. 34 Like all direct thrombin inhibitors, ximelagatran prolongs the activated partial thromboplastin time and international normalized ratio (INR).…”

Section: Ximelagatranmentioning

confidence: 99%

New Anticoagulants for Treatment of Venous Thromboembolism

Weitz

2004

Circulation

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Abstract-Treatment of venous thromboembolism (VTE) usually starts with concomitant administration of heparin or low-molecular-weight heparin (LMWH) and a vitamin K antagonist. The parenteral anticoagulant, which is given for at least 5 days, is stopped once the vitamin K antagonist produces a therapeutic level of anticoagulation. Although the introduction of LMWH has simplified the initial treatment of VTE, problems remain. LMWH must be given by daily subcutaneous (SC) injection and vitamin K antagonists require routine coagulation monitoring, which is inconvenient for patients and physicians. Recently, 3 new anticoagulants have been introduced in an attempt to overcome these limitations. These include fondaparinux and idraparinux, synthetic analogs of the pentasaccharide sequence that mediates the interaction of heparin and LMWH with antithrombin, and ximelagatran, an orally active inhibitor of thrombin. These agents produce a predictable anticoagulant response; thus, routine coagulation monitoring is unnecessary. Because they do not bind to platelets or platelet factor 4, fondaparinux and idraparinux do not cause heparin-induced thrombocytopenia (HIT). Unlike vitamin K antagonists, ximelagatran has a rapid onset of action, thereby obviating the need for concomitant administration of a parenteral anticoagulant when starting treatment. The lack of an antidote for these new agents is a drawback, particularly for idraparinux, which has a long half-life.

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Influence of Age on the Pharmacokinetics and Pharmacodynamics of Ximelagatran, an Oral Direct Thrombin Inhibitor

Abstract: There were no age-dependent differences in the absorption and biotransformation of ximelagatran, and the observed differences in exposure to melagatran can be explained by differences in renal function between the young and older subjects.

Cited by 109 publications

References 26 publications

Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-Glycoprotein-Mediated Excretion

Influence of Erythromycin on the Pharmacokinetics of Ximelagatran May Involve Inhibition of P-Glycoprotein-Mediated Excretion

The status of new anticoagulants

New Anticoagulants for Treatment of Venous Thromboembolism

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