uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Population pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in atrial fibrillation patients receiving long-term anticoagulation therapy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Show others and affiliations
2006 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, Vol. 45, no 8, 803-819 p.Article in journal (Refereed) Published
Abstract [en]

Background: Ximelagatran is an oral direct thrombin inhibitor for the prevention of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.

Objective: To characterise the pharmacokinetics of melagatran in patients with nonvalvular atrial fibrillation (NVAF) receiving long-term treatment for prevention of stroke and systemic embolic events.

Methods: A population pharmacokinetic model was developed based on data from three phase 11 studies (1177 plasma concentration observations in 167 patients, treated for up to 18 months) and confirmed by including data from two phase III studies (8702 plasma concentration observations in 3188 patients, treated for up to 24 months). The impact of individualised dosing on pharmacokinetic variability was evaluated by simulations of melagatran concentrations based on the pharmacokinetic model.

Results: Melagatran pharmacokinetics were consistent across the studied doses and duration of treatment, and were described by a one-compartment model with first-order absorption and elimination. Clearance of melagatran was correlated to creatinine clearance, which was the most important predictor of melagatran exposure (explained 54% of interpatient variance in clearance). Total variability (coefficient of variation) in exposure was 45%; intraindividual variability in exposure was 23%. Concomitant medication with the most common long-term used drugs in the study population had no relevant influence on melagatran pharmacokinetics. Simulations suggested that dose adjustment based on renal function or trough plasma concentration had a minor effect on overall pharmacokinetic variability and the number of patients with high melagatran exposure.

Conclusion: The pharmacokinetics of melagatran in NVAF patients were predictable, and consistent with results from previously studied patient populations. Dose individualisation was predicted to have a low impact on pharmacokinetic variability, supporting the use of a fixed-dose regimen of ximelagatran for long-term anticoagulant therapy in the majority of NVAF patients.

Place, publisher, year, edition, pages
2006. Vol. 45, no 8, 803-819 p.
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-23891DOI: 10.2165/00003088-200645080-00004ISI: 000240023900004PubMedID: 16884319OAI: oai:DiVA.org:uu-23891DiVA: diva2:51665
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2011-06-22Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Hamrén, BengtKarlsson, Mats O.
By organisation
Department of Pharmaceutical Biosciences
In the same journal
Clinical Pharmacokinetics
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 169 hits
ReferencesLink to record
Permanent link

Direct link