Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis.
BACKGROUND
Ximelagatran is a novel, oral direct thrombin inhibitor that is currently being investigated for the prophylaxis and treatment of thromboembolic events. This study evaluated the pharmacokinetics, pharmacodynamics, and clinical effects of melagatran, the active form of ximelagatran, in patients with both deep vein thrombosis (DVT) and pulmonary embolism (PE).


METHODS
In this open-label study, 12 patients received a fixed dose of 48 mg oral ximelagatran twice daily for 6-9 days. Plasma samples were collected for determination of melagatran concentrations and scintigraphic changes and adverse events were recorded.


RESULTS
Peak plasma concentrations of melagatran were attained approximately 2 h after administration of ximelagatran. Melagatran plasma concentration profiles were similar on Days 1, 2, and 6-9. Plasma activated partial thromboplastin time increased following administration of ximelagatran and reached a peak that was approximately twofold higher than the predose activated partial thromboplastin time and correlated with melagatran plasma concentrations (R(2) = 0.69). All but one patient (with malignancy) showed regressed or unchanged lung scintigraphic findings, and six of these demonstrated no, or only minor, perfusion defects at central evaluation after 6-9 days of ximelagatran treatment. Clinical symptoms, including chest pain, dyspnoea, cough, and oedema, and pain in the affected leg, were improved. Ximelagatran was well tolerated with no deaths or severe bleeding events reported during treatment.


CONCLUSIONS
Treatment with a fixed dose of oral ximelagatran, used without routine coagulation monitoring, showed reproducible pharmacokinetics and pharmacodynamics with a rapid onset of action and promising clinical results in patients with pulmonary embolism.
Wåhlander
Karin
K
Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. karin.wahlander@astrazeneca.com
Lapidus
Leif
L
Olsson
Carl-Gustav
CG
Thuresson
Anneli
A
Eriksson
Ulf G
UG
Larson
Göran
G
Eriksson
Henry
H
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001384:Azetidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D001596:Benzylamines; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010599:Pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011655:Pulmonary Embolism / Q000150:complications / Q000188:drug therapy*; D013917:Thrombin / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000150:complications / Q000188:drug therapy*
D001384:Azetidines; D001596:Benzylamines; D005343:Fibrinolytic Agents; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine