Vorapaxar, an oral PAR-1 receptor antagonist, does not affect the pharmacokinetics and pharmacodynamics of warfarin

• Published in: European journal of clinical pharmacology Vol. 68; no. 11; pp. 1509 - 1516
• Main Authors: Kosoglou, Teddy, Zhu, Yali, Xuan, Fengjuan, Black, Laura, Johnson-Levonas, Amy O., Martinho, Monika, Statkevich, Paul, Cutler, David L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.11.2012; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Antagonist drugs; Anticoagulants - adverse effects; Anticoagulants - blood; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Biological Availability; Biomedical and Life Sciences; Biomedicine; Drug Interactions; Drug Monitoring; Half-Life; Humans; International Normalized Ratio; Lactones - adverse effects; Lactones - pharmacology; Male; Medical sciences; Metabolism; Middle Aged; Pharmacokinetics and Disposition; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - pharmacology; Prothrombin Time; Pyridines - adverse effects; Pyridines - pharmacology; Receptor, PAR-1 - antagonists & inhibitors; Statistics as Topic; Stereoisomerism; Warfarin - adverse effects; Warfarin - blood; Warfarin - pharmacokinetics; Warfarin - pharmacology; Young Adult; Warfarin; Pharmacodynamics; PAR-1; Vorapaxar; Pharmacokinetics; Human; Pharmacokinetic pharmacodynamic relationship; Coumarine derivatives; Oral administration; Anticoagulant; Biological activity; PAR1 protease-activated receptor; Antivitamin K; Antagonist
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-012-1271-0

Purpose Vorapaxar is an orally active protease-activated receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet aggregation. This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence/absence of multiple-dose vorapaxar in 12 healthy men. Methods Subjects received two treatments separated by ≥7-day washout: Treatment A warfarin 25 mg (Day 1); Treatment B vorapaxar 2.5 mg/day on Days 1–6 and vorapaxar 40 mg coadministered with warfarin 25 mg (Day 7). R-warfarin, S-warfarin, and prothrombin time (PT) were assayed predose and up to 120 h postdose. Results The geometric mean ratio (GMR) as a percentage (warfarin + vorapaxar/warfarin) was calculated. The GMR (90 % CIs) estimates of C max were 105 (99, 111) and 105 (99, 112) for R- and S-warfarin, respectively. The GMR (90 % CIs) estimates of AUC 0-∞ were 108 (101, 116) and 105 (96, 115) for R- and S-warfarin, respectively. The GMR (95 % CIs) estimates of AUC 0–120 h for PT and INR were 97 (95, 98) and 96 (94, 98), respectively. Conclusion Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin, suggesting that the coadministration of these two drugs or vorapaxar coadministered with other CYP2C9/CYP2C19 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction.