Phase I clinical trial of an antithrombotic drug protocol combining apixaban and clopidogrel in dogs

Abstract

IntroductionCombining an antiplatelet drug, clopidogrel, with the direct oral Factor Xa inhibitor, apixaban, could provide an effective antithrombotic strategy in dogs. Thus, a limited 3 + 3 phase I dose-escalation clinical trial in healthy dogs was conducted to evaluate bleeding (primary end-point) and pharmacodynamic (PD)/pharmacokinetic (PK) parameters (secondary end-point). AnimalsEleven beagle dogs, median body weight 10.2 kg (9.7–10.9 kg), were enrolled. MethodsFour doses of apixaban (three dogs/dose) administered for eight days. Clopidogrel dose was fixed at 18.75 mg per os (PO) q 24 h with escalation of apixaban dose at 5 mg PO q 12 h, 5 mg PO q 8 h, 10 mg PO q 12 h, and 10 mg PO q 8 h. Laboratory testing included fecal occult blood, coagulation parameters, Factor X activity, apixaban concentration, platelet aggregometry, and thromboelastography on days 1, 3, and 8. ResultsEvidence of bleeding was not observed at any dosage. Dose-dependent changes in PD/PK parameters between baseline and 3 h post-medication were observed including a prolongation of prothrombin time, a prolongation of activated partial thromboplastin time, a decrease of Factor X activity level, and increased apixaban concentration. ConclusionsThe combination of apixaban at a dosage range of approximately 0.5 mg/kg PO q 12 h to 1 mg/kg PO q 8 h and clopidogrel at approximately 1.8 mg/kg PO q 24 h did not cause bleeding over a one-week period in healthy dogs. Clinically relevant changes in PD/PK data occur at all dosage levels. This study provides a starting point for longer-term clinical trials to determine safety and efficacy.