Logo: to the web site of Uppsala University

uu.sePublications from Uppsala University
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Ximelagatran in extended secondary prevention of venous thromboembolism: Pharmacokinetics, pharmacodynamics and relationships to clinical events
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Show others and affiliations
Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-94475OAI: oai:DiVA.org:uu-94475DiVA, id: diva2:168335
Available from: 2006-05-02 Created: 2006-05-02 Last updated: 2011-03-01
In thesis
1. Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships
Open this publication in new window or tab >>Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).

Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).

The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.

The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 35
Keywords
Pharmaceutical biosciences, Ximelagatran, pharmacokinetic, pharmacodynamic, activated partial thromboplastin time, utility function, dosing strategy, venous thromboembolism, NONMEM, Farmaceutisk biovetenskap
Identifiers
urn:nbn:se:uu:diva-6872 (URN)91-554-6563-3 (ISBN)
Public defence
2006-05-24, Lecture hall B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 10:00
Opponent
Supervisors
Available from: 2006-05-02 Created: 2006-05-02Bibliographically approved

Open Access in DiVA

No full text in DiVA

Authority records

Karlsson, Mats O.

Search in DiVA

By author/editor
Karlsson, Mats O.
By organisation
Division of Pharmacokinetics and Drug Therapy

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 660 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf