Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers

Sebastian Härtter, Regina Sennewald, Cornelia Schepers, Sybille Baumann, Holger Fritsch, Jeffrey Friedman, Sebastian Härtter, Regina Sennewald, Cornelia Schepers, Sybille Baumann, Holger Fritsch, Jeffrey Friedman

Abstract

Purpose: 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.

Figures

Fig. 1a, b
Fig. 1a, b
Part 2. Effect of comedication with dabigatran on inhibition of platelet aggregation (IPA) by clopidogrel. Comparison between clopidogrel monotherapy and clopidogrel + dabigatran of individual and geometric mean (gMean) AUECτ,ss (a) and Emax,ss values of IPA (b). AUECτ,ss Area under the effect curve of inhibition of platelet aggregation (at steady state), Emax,ss maximum percentage change (compared with baseline) in adenosine triphosphate-induced platelet aggregation of clopidogrel (at steady state)
Fig. 2a–c
Fig. 2a–c
Part 2. Effect of clopidogrel on ecarin clotting time (ECT) ratio (a), activated partial thromboplastin time (aPTT) ratio (b), and TT (anti-factor IIa) ratio (c) after multiple oral administrations of dabigatran etexilate 150 mg twice daily with or without coadministration of repeated doses of 75 mg clopidogrel once daily (300 mg loading dose)

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