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Effect of Casopitant, a Novel NK‐1 Receptor Antagonist, on the Pharmacokinetics and Pharmacodynamics of Steady‐State Warfarin
Author(s) -
Kirby Lyndon C.,
Johnson Brendan M.,
Adams Laurel M.,
Eberwein Derek J.,
Zhang Ke,
Murray Sharon C.,
Lates Christian D.,
Blum Robert A.,
Morris Shan R.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009346965
Subject(s) - warfarin , pharmacodynamics , regimen , pharmacokinetics , medicine , pharmacology , cyp2c9 , anesthesia , cytochrome p450 , atrial fibrillation , metabolism
Casopitant, a novel NK‐1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy‐induced nausea and vomiting, is a weak to moderate inhibitor of CYP3A and a moderate inducer of CYP2C9 in vitro. Furthermore, both CYP enzymes are involved in the metabolism of R‐ and S‐warfarin, respectively. This clinical study was conducted to explore the potential drug—drug interaction between casopitant and warfarin. In total, 97 healthy participants were enrolled and 54 completed the study. Participants received individualized daily dosing of warfarin to an international normalized ratio (INR) of 1.3 to 2.3 over a 14‐day period (period 1). Immediately following period 1, participants entered period 2 and were randomized to receive either regimen A (oral casopitant [150 mg day 1, 50 mg days 2 and 3] and warfarin [days 1–10]) or regimen B (oral casopitant 60 mg and warfarin [days 1–14]). INR assessments were performed daily. The steady‐state C max and AUC of R‐ and S‐warfarin were not altered by regimen A, but R‐warfarin AUC was increased 1.31‐fold (90% confidence interval [CI]: 1.22, 1.41), and S‐warfarin AUC was increased 1.27‐fold (90% CI: 1.18, 1.38) on day 14 in regimen B. Steady‐state INR values were not affected by either casopitant regimen.