title: Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects.
abstract: OBJECTIVE
  Apixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability.
  
  
  METHODS
  Fifty-four healthy subjects were enrolled [18 each into low (≤50 kg), reference (65-85 kg) and high (≥120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored.
  
  
  RESULTS
  Compared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8-51%] and 20% (90% CI: 11-42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC(0,∞)), respectively, and high body weight had approximately 31% (90% CI: 18-41%) and 23% (90% CI: 9-35%) lower apixaban Cmax and AUC(0,∞) , respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study.
  
  
  CONCLUSIONS
  The modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.
authors.affiliation: Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb Company, Princeton, NJ, USA.
authors.forename: Vijay V
authors.initials: VV
authors.lastname: Upreti
authors.forename: Jessie
authors.initials: J
authors.lastname: Wang
authors.forename: Yu Chen
authors.initials: YC
authors.lastname: Barrett
authors.forename: Wonkyung
authors.initials: W
authors.lastname: Byon
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Boyd
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.forename: Frank P
authors.initials: FP
authors.lastname: LaCreta
authors.forename: Charles E
authors.initials: CE
authors.lastname: Frost
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D015992:Body Mass Index; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D056865:Ideal Body Weight; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000097:blood / Q000378:metabolism*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D013851:Thinness / Q000097:blood / Q000378:metabolism*; D013927:Thrombosis / Q000517:prevention & control; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: anticoagulation; apixaban; body weight; factor Xa inhibitor; pharmacodynamics; pharmacokinetics