Sökning: onr:"swepub:oai:DiVA.org:uu-6872" >
Direct Thrombin Inh...
Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships
-
- Cullberg, Marie, 1958- (författare)
- Uppsala universitet,Avdelningen för farmakokinetik och läkemedelsterapi
-
Karlsson, Mats O. (preses)
-
Eriksson, Ulf G. (preses)
-
visa fler...
-
- Holford, Nick H.G. Associate Professor (opponent)
- Department of Pharmacology and Clinical Pharmacology, Auckland
-
visa färre...
-
(creator_code:org_t)
- ISBN 9155465633
- Uppsala : Acta Universitatis Upsaliensis, 2006
- Engelska 71 s.
-
Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 35
- Relaterad länk:
-
https://uu.diva-port... (primary) (Raw object)
-
visa fler...
-
https://uu.diva-port...
-
https://urn.kb.se/re...
-
visa färre...
Abstract
Ämnesord
Stäng
- 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.
Nyckelord
- Pharmaceutical biosciences
- Ximelagatran
- pharmacokinetic
- pharmacodynamic
- activated partial thromboplastin time
- utility function
- dosing strategy
- venous thromboembolism
- NONMEM
- Farmaceutisk biovetenskap
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
Hitta via bibliotek
Till lärosätets databas