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

Abstract

PurposeTo 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.MethodsThis 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.ResultsBioavailability 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 AUCτ,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 (AUCτ,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 AUC0−24 was 103%; 90% CI 80.3–131%), as did its pharmacodynamic effects on the inhibition of platelet aggregation.ConclusionsWhen 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00228-012-1304-8) contains supplementary material, which is available to authorized users.

A proposal for dose‐adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time

“…While brief descriptions of plasma dabigatran assays have been reported in several clinical papers , only Delavenne et al . have published a comprehensive dabigatran assay method detailing the development and validation procedures in accordance with FDA guidelines .…”

“…Reports of the contribution of the dabigatran glucuronides to total active drug‐related exposure in plasma from dabigatran etexilate range from 10 to 35% , with no apparent influence of mild to severe renal or moderate hepatic impairment . The range is only slightly narrower (15–35%) when the reports are restricted to those involving healthy young individuals who were administered a single dabigatran etexilate dose of 150 mg . However, the variability of the contribution of the glucuronides to overall drug exposure has been reported to be low in healthy young individuals, as reflected by a coefficient of variation (CV) of 8–10% .…”

“…For example, the glucuronides may be unstable during sample storage . This is difficult to establish as the glucuronides were not assayed directly in any of the reported studies . Instead, these were inferred from the difference in plasma dabigatran concentrations before and after alkalinization (hydrolyzing the glucuronides to dabigatran) .…”

“…Other P‐glycoprotein inhibitors (with reported mean AUC(0,∞) ratio) include: ketoconazole (2.5) ; dronedarone (2.0) ; amiodarone (1.6) ; clarithromycin (1.5) ; quinidine (1.5) ; ticagrelor (1.5) [72] loading doses of clopidogrel (1.3) .…”

Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions

“…Dabigatran and clopidogrel had no clinically relevant pharmacokinetic or pharmacodynamic effects on each other. However, if a loading dose of clopidogrel (300 mg or 600 mg) was administered, dabigatran AUC and C max at steady state increased by 30–40% . For drug interactions with P‐gp inducers and inhibitors, the maximum increase in dabigatran bioavailability was observed with ketoconazole (~150%) .…”