Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers.
OBJECTIVE
To evaluate the pharmacokinetic and pharmacodynamic effects of concomitant administration of single loading doses of clopidogrel or multiple doses of clopidogrel with multiple doses of dabigatran etexilate.


METHODS
This was an open-label trial in healthy male subjects. In part 1 (pilot, n = 8) and part 3 (n = 12), a single dose of clopidogrel (300 or 600 mg, respectively) was given concomitantly with dabigatran etexilate at steady state; part 2 was a randomized, multiple-dose, crossover study with the test treatment being clopidogrel at steady state [300 mg loading dose on day 1, then 75 mg once daily (qd)] with concomitant dabigatran.


RESULTS
Bioavailability was moderately increased when a loading dose of clopidogrel (300 mg in part 1 and 600 mg in part 3) was administered concomitantly with dabigatran etexilate 150 mg twice daily (bid). Test/reference ratios for AUC(τ,ss) were 135% (90% CI 107-169%) and 132% (90% CI 112-156%), respectively. Steady-state dosing of clopidogrel 75 mg qd and dabigatran etexilate 150 mg bid (part 2) demonstrated minor effects on dabigatran pharmacokinetics (AUC(τ,ss) ratio test/reference: 91.9%, 90% CI 78.7-107%) or its pharmacokinetic/pharmacodynamic relationships (activated partial thromboplastin time, ecarin clotting time, thrombin time). Similarly, clopidogrel bioavailability remained unchanged by chronic administration of dabigatran etexilate (part 3: ratio test/reference for AUC(0-24) was 103%; 90% CI 80.3-131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation.


CONCLUSIONS
When given concomitantly, dabigatran etexilate and clopidogrel at clinically relevant doses did not appear to have significant effects on the pharmacokinetic and pharmacodynamic profiles of either agent.
Boehringer Ingelheim Pharma GmbH & Co. KG, Translational Medicine, Biberach an der Riss, Germany. Sebastian.haertter@boehringer-ingelheim.com
Sebastian
S
Härtter
Regina
R
Sennewald
Cornelia
C
Schepers
Sybille
S
Baumann
Holger
H
Fritsch
Jeffrey
J
Friedman
D000328:Adult; D000704:Analysis of Variance; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D000077144:Clopidogrel; D018592:Cross-Over Studies; D000069604:Dabigatran; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005858:Germany; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010314:Partial Thromboplastin Time; D010865:Pilot Projects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013918:Thrombin Time; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
D000991:Antithrombins; D001562:Benzimidazoles; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D000077144:Clopidogrel; D000069604:Dabigatran; D013988:Ticlopidine