Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban

• Published in: Journal of clinical pharmacology Vol. 56; no. 5; p. 637
• Main Authors: Chang, Ming, Yu, Zhigang, Shenker, Andrew, Wang, Jessie, Pursley, Janice, Byon, Wonkyung, Boyd, Rebecca A, LaCreta, Frank, Frost, Charles E
• Format: Journal Article
• Language: English
• Published: England 01.05.2016
• Subjects: Adult; Aged; Aged, 80 and over; Area Under Curve; Creatinine - analysis; Factor Xa - analysis; Factor Xa Inhibitors - adverse effects; Factor Xa Inhibitors - blood; Factor Xa Inhibitors - pharmacokinetics; Factor Xa Inhibitors - pharmacology; Female; Humans; International Normalized Ratio; Male; Middle Aged; Pyrazoles - adverse effects; Pyrazoles - blood; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Pyridones - adverse effects; Pyridones - blood; Pyridones - pharmacokinetics; Pyridones - pharmacology; Renal Insufficiency - metabolism; pharmacokinetics; anticoagulant; apixaban; pharmacodynamics; renal impairment
• ISSN: 1552-4604
• DOI: 10.1002/jcph.633

This open-label study evaluated apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed. Secondary objectives included assessment of safety and tolerability as well as international normalized ratio (INR) and anti-factor Xa activity as pharmacodynamic endpoints. The regression analysis showed that decreasing renal function resulted in modestly increased apixaban exposure (AUC∞ increased by 44% in severe impairment with a 24-hour CLcr of 15 mL/min, compared with subjects with normal renal function), but it did not affect Cmax or the direct relationship between apixaban plasma concentration and anti-factor Xa activity or INR. The assessment of renal function measured by iohexol clearance, Cockcroft-Gault, and MDRD was consistent with that determined by 24-hour CLcr . Apixaban was well tolerated in this study. These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone.