Safety and Pharmacokinetics of DS‐1040 Drug‐Drug Interactions With Aspirin, Clopidogrel, and Enoxaparin

Abstract DS‐1040, a novel low‐molecular‐weight inhibitor of activated thrombin‐activatable fibrinolysis inhibitor, is under development for the treatment of thromboembolic diseases including venous thromboembolism and acute ischemic stroke. Here we describe the results of 3 studies that evaluated the safety and tolerability of DS‐1040 along with the effect on DS‐1040 pharmacokinetic (PK) parameters, when dosed alone or when coadministered with aspirin (NCT02071004), clopidogrel (NCT02560688), or enoxaparin in healthy subjects. Concomitant administration of single‐dose DS‐1040 with multiple‐dose aspirin, multiple‐dose clopidogrel, or single‐dose enoxaparin, consistent with clinically relevant dose regimens, was safe and well tolerated with no serious treatment‐emergent adverse events (TEAEs), TEAEs leading to discontinuation, bleeding‐related TEAEs, and no significant changes in coagulation parameters. DS‐1040 did not prolong bleeding time when administered concomitantly with aspirin or clopidogrel. In the aspirin study, DS‐1040 PK was evaluated following the concomitant administration with multiple‐dose aspirin, where the plasma DS‐1040 exposure (peak plasma concentration [C max ] and area under the concentration‐time curve [AUC inf ]) was to be similar to the data previously published in the first‐in‐human study of DS‐1040 in healthy subjects. The PK parameters of DS‐1040 coadministered with clopidogrel were similar to those of DS‐1040 alone, with small increases in geometric means for C max (7%) and AUC last (9%). When coadministered with enoxaparin, the PK parameters of DS‐1040 were not affected (1.1% and 1.5% decreases in geometric means for C max and AUC last , respectively). Therefore, concomitant administration of DS‐1040 and clopidogrel or enoxaparin did not demonstrate PK drug‐drug interactions.