Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid.
OBJECTIVE
The aim of this study was to evaluate the effect of acetylsalicylic acid (ASA or aspirin) on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran in healthy volunteers. Melagatran is the active form of the oral direct thrombin inhibitor, ximelagatran.


METHODS
This was a double-blind, randomised, two-way, crossover study consisting of two treatment periods separated by a washout period of at least 2 weeks. Twelve subjects received, in a randomised order, either melagatran plus ASA in the first treatment period and melagatran plus placebo in the second treatment period or vice versa. Two single doses of ASA were given, first 450 mg on the day before (day 1) and then 150 mg just before administration of melagatran on day 2. Melagatran 4.12 mg was administered as an intravenous (i.v.) infusion over 4 h on day 2 of both treatment periods. Serial blood samples were collected over the course of the study for the determination of melagatran plasma concentration and coagulation analyses [activated partial thromboplastin time (APTT) and activated clotting time (ACT)]. Capillary bleeding time was measured before ASA/placebo on day 1 and before and after the start of the melagatran infusion on day 2.


RESULTS
The plasma concentration of melagatran during the i.v. infusion was maintained at about 0.2 micro mol/l, and ASA did not influence the PK parameters of melagatran. APTT and ACT increased with increasing melagatran plasma concentration, and the observed increases were similar whether melagatran was administered on top of ASA or placebo. Administration of ASA significantly prolonged the capillary bleeding time (by 41% relative to placebo). Melagatran also prolonged the bleeding time significantly (by 25% relative to placebo alone), but this prolongation was not significantly different from the observed prolongation when melagatran was administered on top of ASA (by 17% relative to ASA alone).


CONCLUSIONS
In young healthy volunteers, ASA had no effect on the PK or PD properties of melagatran at the studied dose. That the combination of ximelagatran with ASA may be used with acceptable safety must be verified in the relevant patient populations.
Fager
Gunnar
G
Experimental Medicine, AstraZeneca RD Mölndal, 431 83 Mölndal, Sweden. Gunnar.B.Fager@astrazeneca.com
Cullberg
Marie
M
Eriksson-Lepkowska
Maria
M
Frison
Lars
L
Eriksson
Ulf G
UG
D000284:Administration, Oral; D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D001384:Azetidines / Q000008:administration & dosage; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010314:Partial Thromboplastin Time; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014914:Whole Blood Coagulation Time
D001384:Azetidines; D001596:Benzylamines; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D001241:Aspirin; D005998:Glycine