Armetheon, Inc.

Tecarfarin is a vitamin K antagonist (VKA) with reduced propensity for drug interactions. To evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety of tecarfarin, we performed single ascending dose (SAD) (n=66), multiple ascending dose (MAD) (n=43), and tecarfarin versus warfarin (n=28) studies in human volunteers. In the SAD, tecarfarin was administered to 5 of 6 subjects (1 received placebo) in each of 11 cohorts. AUC0-∞ exhibited linearity and dose proportionality. Elimination T1/2 ranged from 87–136 hours (h) across all doses. In the MAD, tecarfarin was administered to 5 of 6 volunteers in each of 7 cohorts. The starting dose was continued until the subject’s INR reached the target range (TR) of 1.7 to 2.0. Dosing was down-titrated if the TR was achieved. Elimination T1/2 ranged from 107–140 h. Doses <10 mg had insignificant effect on INR. Higher doses raised INRs and required down-titration to maintain the TR. Steady state INR dosing was 10–20 mg. INR declined promptly after discontinuation. In the comparative study, subjects received tecarfarin or warfarin and dose titrated to a TR of 1.5–2.0. Mean dose after TR was achieved was 13.9 mg (range 10.0–25.5 mg) for tecarfarin and 5.3 mg (range 2.5–9.0 mg) for warfarin. At similar INR levels, the concentration of coagulation factors II, VII, IX, and X were similar for tecarfarin and warfarin. Tecarfarin was tolerated well without serious adverse events in all three studies.Supplementary Material to this article is available online at www.thrombosis-online.com.