No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.
BACKGROUND
The oral direct thrombin inhibitor ximelagatran is a new class of anticoagulant currently in clinical development for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form melagatran.


OBJECTIVE
To investigate the influence of mild-to-moderate hepatic impairment on the pharmacokinetic and pharmacodynamic properties of ximelagatran.


METHODS
Nonblinded, nonrandomised study.


METHODS
Twelve volunteers with mild-to-moderate hepatic impairment (classified as Child-Pugh A or B) and 12 age-, weight-, and sex-matched control volunteers with normal hepatic function.


METHODS
Volunteers received a single oral dose of ximelagatran 24mg. Plasma and urine samples were collected for pharmacokinetic and pharmacodynamic analyses.


RESULTS
The absorption and bioconversion of ximelagatran to melagatran were rapid in both groups. The maximum plasma concentration of melagatran (Cmax) was achieved 2-3 hours after administration; the mean elimination half-life (t1/2z) was 3.6 hours for hepatically impaired volunteers and 3.1 hours for the control volunteers. The area under the plasma concentration-time curve (AUC) and Cmax of melagatran in volunteers with hepatic impairment were 11 and 25% lower than in control volunteers, respectively. However, after correcting for the higher renal function (i.e. higher calculated creatinine clearance) in the hepatically impaired volunteers, the ratio of melagatran AUC for hepatically impaired/control volunteers was 0.98 (90% CI 0.80, 1.22), suggesting that mild-to-moderate hepatic impairment had no influence on the pharmacokinetics of ximelagatran. Melagatran was the predominant compound in urine, accounting for 13-14% of the ximelagatran dose. Renal clearance of melagatran was 13% higher in hepatically impaired than in control volunteers. There were no significant differences between the two groups in the concentration-response relationship between plasma melagatran concentration and activated partial thromboplastin time (APTT). Baseline prothrombin time (PT) was slightly longer in the hepatically impaired patients than in the control volunteers, probably reflecting a slight decrease in the activity of coagulation factors. However, when concentrations of melagatran were at their peak, the increase in PT from baseline values was the same in both groups. Capillary bleeding time was measured in the hepatically impaired patients only, and was not increased by ximelagatran. Ximelagatran was well tolerated in both groups.


CONCLUSIONS
There were no differences in the pharmacokinetic or pharmacodynamic properties of melagatran following oral administration of ximelagatran between the hepatically impaired and control volunteers. These findings suggest that dose adjustment for patients with mild-to-moderate impairment of hepatic function is not necessary.
Wåhlander
Karin
K
Experimental Medicine, AstraZeneca R&D, Mölndal, Sweden. karin.wahlander@astrazeneca.com
Eriksson-Lepkowska
Maria
M
Frison
Lars
L
Fager
Gunnar
G
Eriksson
Ulf G
UG
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000578:Amidines / Q000097:blood; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001596:Benzylamines; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood; D006207:Half-Life; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011517:Prothrombin Time; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000578:Amidines; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C479417:N-hydroxymelagatran; D011355:Prodrugs; C479418:ethyl melagatran; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine