Studies of interaction of a low-molecular-weight heparinoid (Org 10172) with cloxacillin and ticarcillin in healthy male volunteers

Abstract

Pharmacokinetic and pharmacodynamic interactions between Org 10172 (intravenous bolus injection of 3,250 anti-Xa units), which is a low-molecular-weight heparinoid, cloxacillin (500 mg orally four times daily for 3 days), and ticarcillin (4,000 mg intravenously four times daily for 2 days) were evaluated in two separate studies with healthy male volunteers (n = 18). Both cloxacillin and ticarcillin caused a significant increase in elimination half-life of anti-Xa activity, i.e., from 31 +/- 10 to 54 +/- 23 h and from 27 +/- 6 to 42 +/- 13 h, respectively (P less than 0.05). Ticarcillin decreased clearance (11%) and increased apparent volume of distribution (35%) (P less than 0.05), while for cloxacillin, these differences did not reach statistical significance. These changes in disposition of Org 10172 by the penicillins were not accompanied by important pharmacodynamic changes as evaluated by coagulation tests, platelet aggregation, and bleeding time. Cloxacillin appeared to influence blood coagulation (prolongation of the activated partial thromboplastin time and shortening of thrombin time; P less than 0.05) and facilitated thrombin-induced platelet aggregation, which coincided with a shorter bleeding time during the combined treatment in comparison with the time during treatment with Org 10172 alone (P less than 0.05). In conclusion, the disposition of Org 10172 was slightly changed by cloxacillin and ticarcillin, and, unexpectedly, cloxacillin appeared to have mild procoagulant effects.