PMID- 23451769
OWN - NLM
STAT- MEDLINE
DCOM- 20140804
LR  - 20220330
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 76
IP  - 5
DP  - 2013 Nov
TI  - Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, 
      a factor Xa inhibitor, in healthy subjects.
PG  - 776-86
LID - 10.1111/bcp.12106 [doi]
AB  - AIM: Apixaban is an oral factor Xa inhibitor approved for stroke prevention in 
      atrial fibrillation and thromboprophylaxis in patients who have undergone 
      elective hip or knee replacement surgery and under development for treatment of 
      venous thromboembolism. This study examined the safety, pharmacokinetics and 
      pharmacodynamics of multiple dose apixaban. METHOD: This double-blind, 
      randomized, placebo-controlled, parallel group, multiple dose escalation study 
      was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice 
      daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within 
      each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 
      days. Subjects underwent safety assessments and were monitored for adverse events 
      (AEs). Blood samples were taken to measure apixaban plasma concentration, 
      international normalized ratio (INR), activated partial thromboplastin time 
      (aPTT) and modified prothrombin time (mPT). RESULTS: Forty-eight subjects were 
      randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 
      2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose 
      limiting AEs were observed. Apixaban maximum plasma concentration was achieved 
      ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban 
      steady-state concentrations were reached by day 3, with an accumulation index of 
      1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. 
      Clotting times showed dose-related increases tracking the plasma 
      concentration-time profile. CONCLUSION: Multiple oral doses of apixaban were safe 
      and well tolerated over a 10-fold dose range, with pharmacokinetics with low 
      variability and concentration-related increases in clotting time measures.
CI  - (c) 2013 Bristol-Myers Squibb Co. British Journal of Clinical Pharmacology (c) 2013 
      The British Pharmacological Society.
FAU - Frost, Charles
AU  - Frost C
AD  - Bristol-Myers Squibb, Princeton, NJ, USA.
FAU - Nepal, Sunil
AU  - Nepal S
FAU - Wang, Jessie
AU  - Wang J
FAU - Schuster, Alan
AU  - Schuster A
FAU - Byon, Wonkyung
AU  - Byon W
FAU - Boyd, Rebecca A
AU  - Boyd RA
FAU - Yu, Zhigang
AU  - Yu Z
FAU - Shenker, Andrew
AU  - Shenker A
FAU - Barrett, Yu Chen
AU  - Barrett YC
FAU - Mosqueda-Garcia, Rogelio
AU  - Mosqueda-Garcia R
FAU - Lacreta, Frank
AU  - Lacreta F
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Factor Xa Inhibitors)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyridones)
RN  - 3Z9Y7UWC1J (apixaban)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - *Factor Xa Inhibitors
MH  - Fibrinolytic Agents/*administration & dosage/pharmacokinetics/pharmacology
MH  - Humans
MH  - International Normalized Ratio
MH  - Male
MH  - Partial Thromboplastin Time
MH  - Prothrombin Time
MH  - Pyrazoles/*administration & dosage/pharmacokinetics/pharmacology
MH  - Pyridones/*administration & dosage/pharmacokinetics/pharmacology
MH  - Young Adult
PMC - PMC3853536
OTO - NOTNLM
OT  - anticoagulant/thrombolytic drugs
OT  - apixaban
OT  - cardiovascular pharmacology
OT  - coagulation/fibrinolysis
OT  - pharmacokinetics
EDAT- 2013/03/05 06:00
MHDA- 2014/08/05 06:00
PMCR- 2014/11/01
CRDT- 2013/03/05 06:00
PHST- 2012/09/21 00:00 [received]
PHST- 2013/02/22 00:00 [accepted]
PHST- 2013/03/05 06:00 [entrez]
PHST- 2013/03/05 06:00 [pubmed]
PHST- 2014/08/05 06:00 [medline]
PHST- 2014/11/01 00:00 [pmc-release]
AID - 10.1111/bcp.12106 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2013 Nov;76(5):776-86. doi: 10.1111/bcp.12106.