title: Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.
abstract: 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.
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Shenker
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Jessie
authors.initials: J
authors.lastname: Wang
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.affiliation: Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc., Groton, CT, USA.
authors.forename: Wonkyung
authors.initials: W
authors.lastname: Byon
authors.affiliation: Global Innovative Pharma Business Clinical Pharmacology, Pfizer Inc., Groton, CT, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Boyd
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: LaCreta
authors.affiliation: At the time of research, Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Frost
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003404:Creatinine / Q000032:analysis; D015951:Factor Xa / Q000032:analysis; D065427:Factor Xa Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D051437:Renal Insufficiency / Q000378:metabolism*
chemical_list: D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D003404:Creatinine; D015951:Factor Xa
keywords: anticoagulant; apixaban; pharmacodynamics; pharmacokinetics; renal impairment