Pharmacokinetics and pharmacodynamics of tecarfarin, a novel vitamin K antagonist oral anticoagulant.
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 T1/2ranged 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 T1/2ranged 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.
Detlef
D
Albrecht
David
D
Ellis
Daniel M
DM
Canafax
Daniel
D
Combs
Pascal
P
Druzgala
Peter G
PG
Milner
Mark G. Midei, MD, Armetheon, Inc., 490 North McCarthy Blvd., Suite 200, Milpitas, CA 95035, USA, Tel.: +1 650 646 3898, Fax: +1 650 452 7859, E-mail: mmidei@armetheon.com.
Mark G
MG
Midei
D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001777:Blood Coagulation / Q000187:drug effects*; D001779:Blood Coagulation Factors / Q000378:metabolism; D003374:Coumarins / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013781:Texas; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult; D005466:Fluorocarbons
D000925:Anticoagulants; D001565:Benzoates; D001779:Blood Coagulation Factors; D003374:Coumarins; D014812:Vitamin K; D014859:Warfarin; C547288:tecarfarin; D005466:Fluorocarbons
Tecarfarin; VKA; pharmacodynamics; pharmacokinetics; warfarin