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Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects

  • Pharmokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran.

Methods

In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing.

Results

The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t 1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t 1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls.

Conclusion

The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.

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Acknowledgements

The administrative work of Carola Fuchs, RN, during the study is gratefully acknowledged. This study was funded by AstraZeneca, Mölndal, Sweden.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, University of Vienna, Vienna, Austria

    Michael Wolzt

  2. AstraZeneca R&D Mölndal, Mölndal, Sweden

    Maria Wollbratt, Mia Svensson, Karin Wåhlander, Margaretha Grind & Ulf G. Eriksson

  3. Experimental Medicine, AstraZeneca R&D Mölndal, S-431 83 , Mölndal, Sweden

    Ulf G. Eriksson

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  1. Michael Wolzt
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  2. Maria Wollbratt
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  3. Mia Svensson
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  4. Karin Wåhlander
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  5. Margaretha Grind
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  6. Ulf G. Eriksson
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Correspondence to Ulf G. Eriksson.

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Wolzt, M., Wollbratt, M., Svensson, M. et al. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects. Eur J Clin Pharmacol 59, 537–543 (2003). https://doi.org/10.1007/s00228-003-0667-2

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  • DOI: https://doi.org/10.1007/s00228-003-0667-2

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