Lack of Clinically Significant Interactions Between the Subcutaneously Administered Direct Thrombin Inhibitor Desirudin and Orally Administered Warfarin Upon the International Normalized Ratio.
Authors: Levy Jerrold , Kurz Michael , Whelton Andrew 
Published: October 2019

Abstract
Abstract 3131
Poster Board III-68

Background
Direct thrombin inhibitors (DTIs) have heterogeneous effects on the international normalized ratio (INR). Argatroban, in particular, has a clinically significant impact on the INR that complicates transition to warfarin therapy (Hirsh J. Chest 2008;133:141-149). Desirudin is a potent, subcutaneously administered DTI approved for the prophylaxis of deep vein thrombosis (DVT), in patients undergoing elective hip replacement surgery. While the pharmacologic effects and clinical utility of desirudin have been extensively studied, the quantitative pharmacodynamic effects associated with the concomitant use of desirudin and warfarin have not been previously reported. The primary objective of this phase 1 study was to determine the safety and tolerability of the combination of desirudin when coadministered with warfarin.

Methods
This was an open-label, nonrandomized, single-center trial involving 12 healthy adult male volunteers. Potential pharmacodynamic interactions between desirudin and warfarin were assessed by comparing the effects of each drug on prothrombin time (PT; as measured by INR) and activated partial thromboplastin time (aPTT) when each drug was administered alone and during coadministration. The study was divided into 2 dosing periods, A and B. In dosing period A, aPTT and PT (INR) profiles were assessed for warfarin 10 mg given once daily for 3 days. In dosing period B, aPTT and PT (INR) profiles were assessed for a single SC 0.3 mg/kg dose of desirudin given alone, then for the coadministration of SC desirudin 0.3 mg/kg twice daily with orally administered warfarin 10 mg once daily for 3 days. A 2-week washout period occurred between dosing periods. During dosing period A, venous blood samples were collected prior to dosing on day 1 and at 4, 8, 12, and 24 hours postdose on days 1–3; a final sample was obtained 48 hours after the last dose of warfarin. During dosing period B, blood samples were collected prior to the first dose of desirudin given alone and at 4, 8, 12, and 24 hours postdose. During the 3 days of concomitant drug administration, samples were collected at 4, 8, and 12 hours after each dose of desirudin and warfarin; final samples were obtained at 24 and 48 hours after the last dose of desirudin. With regards to the coagulation parameters (aPTT and PT), summary statistics (mean, standard deviation, median, minimum and maximum) were calculated for the absolute value and the ratio of the absolute value to baseline for each evaluated time point, the difference to baseline and the difference between desirudin treatment alone and in combination with warfarin.

Results
An additive effect was observed with the coadministration of desirudin and warfarin. The aPTT increased by a median of 18.3 seconds (range: 1.5–26.3 seconds, P<.01) during coadministration of desirudin and warfarin compared with the administration of desirudin alone. The INR also increased by a median of 1.1 (range: 0.6–1.8, P<.01) during the coadministration of the study drugs. Both study drugs were well tolerated, and the observed effects of coadministration on aPTT and INR were not considered by investigators to be clinically significant.

Conclusion
The coadministration of desirudin and warfarin has a moderate effect on aPTT and INR levels in healthy adult males. The observed effects on aPTT and INR are similar to those reported for lepirudin on these parameters. Desirudin appears to have lesser effects on INR compared with argatroban (Gosselin RC et al. Am J Clin Pathol, 2004;121:593-599), that may facilitate transitioning to warfarin in patients requiring longer term anticoagulation.

Disclosures
Kurz: Canyon Pharmaceuticals: Employment, Equity Ownership. Whelton:Canyon Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.