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.

Carboxypeptidase U (CPU, TAFIa, CPB2) in Thromboembolic Disease: What Do We Know Three Decades after Its Discovery?

“…Furthermore, concomitant administration of a single IV dose of DS-1040 with oral clopidogrel or i.m. enoxaparin did not result in measurable PK drug-drug interactions [166]. Two phase Ib/II clinical trials evaluating the safety, tolerability and PK/PD of DS-1040 in subjects with acute ischemic stroke (ASSENT; NCT02586233 and NCT03198715) and acute submassive pulmonary embolism (NCT02923115) respectively have recently been completed.…”

Endogenous fibrinolysis inhibitors in acute coronary syndrome

“…Other agents that are under evaluation and may have potential profibrinolytic effects include the low-molecular weight imidazole-derivative DS-1040 [96] , [97] , [98] , [99] , monoclonal antibodies and nanobodies that are highly-specific against TAFI [100] , [101] , [102] , monoclonal antibodies to alpha2-antiplasmin [103] , [104] and PAI-1 [105] , the complement C3 inhibitor cyclic peptide compstatin [106] , [107] , PAI-1 antagonist PAItrap [108] and clopidogrel [109] , [110] , microparticle release suppression by clopidogrel [111] , [112] and rosuvastatin [113] , antisense oligonucleotide to lower elevated lipoprotein (a) levels [114] , and the antiplatelet agents aspirin and cangrelor [115] , [116] .…”

Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients

“…However, profibrinolytic therapy may lead to an increased bleeding risk. So far, CPU inhibition has not been associated with major bleeding complications but has not yet been tested in the clinical setting in combination with rtPA [17][18][19][20][21]. When determining the dosage and timeframe of the administration of an inhibitor, it is crucial to take into account the kinetics and the amplitude of CPU activation and inactivation (CPUi) during fibrinolysis.…”