PMID- 26977298
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20160315
LR  - 20210109
IS  - 2052-1707 (Print)
IS  - 2052-1707 (Electronic)
IS  - 2052-1707 (Linking)
VI  - 4
IP  - 1
DP  - 2016 Feb
TI  - Preclinical and translational evaluation of coagulation factor IXa as a novel 
      therapeutic target.
PG  - e00207
LID - 10.1002/prp2.207 [doi]
LID - e00207
AB  - The benefits of novel oral anticoagulants are hampered by bleeding. Since 
      coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and 
      intermediate levels have been associated with reduced incidence of thrombotic 
      events, we evaluated the viability of fIXa as an antithrombotic target. We 
      applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to 
      predict the therapeutic window (TW) associated with a selective small molecule 
      inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 
      21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 
      4.3 nmol/L). Concentrations encompassing the minimal clinical plasma 
      concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested 
      in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) 
      models. An I max and a linear model were used to fit clot weight (CW) and CBT. 
      The following differences in biology were observed: (1) antithrombotic activity 
      and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 
      and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for 
      fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that 
      noninferiority was observed for concentrations of CPD1 that provided between 86% 
      and 96% EO and that superior TW existed between 86% and 90% EO. These findings 
      were confirmed in a study comparing short interfering (si)RNA-mediated knockdown 
      (KD) modulation of fIX and fX mRNA. In summary, using principles of translational 
      biology to relate preclinical markers of efficacy and safety to clinical doses of 
      apixaban, we found that modulation of fIXa can be superior to apixaban.
FAU - Ankrom, Wendy
AU  - Ankrom W
AD  - PPDM Merck & Co., Inc. Rahway New Jersey.
FAU - Wood, Harold B
AU  - Wood HB
AD  - Discovery Chemistry Merck & Co., Inc. Rahway New Jersey.
FAU - Xu, Jiayi
AU  - Xu J
AD  - Discovery Chemistry Merck & Co., Inc. Rahway New Jersey.
FAU - Geissler, Wayne
AU  - Geissler W
AD  - In Vitro Pharmacology Merck & Co., Inc. Kenilworth New Jersey.
FAU - Bateman, Tom
AU  - Bateman T
AD  - PPDM Merck & Co., Inc. Kenilworth New Jersey.
FAU - Chatterjee, Manash S
AU  - Chatterjee MS
AD  - PPDM Merck & Co., Inc. Rahway New Jersey.
FAU - Feng, Kung-I
AU  - Feng KI
AD  - Discovery Pharmaceutical Sciences Merck & Co., Inc. Rahway New Jersey.
FAU - Metzger, Joseph M
AU  - Metzger JM
AD  - In Vitro Pharmacology Merck & Co., Inc. Kenilworth New Jersey.
FAU - Strapps, Walter R
AU  - Strapps WR
AD  - RNA Therapeutics Merck & Co., Inc. West Point Pennsylvania.
FAU - Tadin-Strapps, Marija
AU  - Tadin-Strapps M
AD  - Genetics and Pharmacogenomics Merck & Co., Inc. Boston Massachusetts.
FAU - Seiffert, Dietmar
AU  - Seiffert D
AD  - Cardiometabolic Disease Merck & Co., Inc. Kenilworth New Jersey.
FAU - Andre, Patrick
AU  - Andre P
AD  - Cardiometabolic Disease Merck & Co., Inc. Kenilworth New Jersey.
LA  - eng
PT  - Journal Article
DEP - 20160115
PL  - United States
TA  - Pharmacol Res Perspect
JT  - Pharmacology research & perspectives
JID - 101626369
PMC - PMC4777260
OTO - NOTNLM
OT  - anticoagulation
OT  - factor IX
OT  - factor IXa
OT  - stroke prevention in atrial fibrillation
OT  - thrombosis
OT  - translational PK/PD.
EDAT- 2016/03/16 06:00
MHDA- 2016/03/16 06:01
PMCR- 2016/01/15
CRDT- 2016/03/16 06:00
PHST- 2015/11/13 00:00 [received]
PHST- 2015/11/19 00:00 [accepted]
PHST- 2016/03/16 06:00 [entrez]
PHST- 2016/03/16 06:00 [pubmed]
PHST- 2016/03/16 06:01 [medline]
PHST- 2016/01/15 00:00 [pmc-release]
AID - PRP2207 [pii]
AID - 10.1002/prp2.207 [doi]
PST - epublish
SO  - Pharmacol Res Perspect. 2016 Jan 15;4(1):e00207. doi: 10.1002/prp2.207. 
      eCollection 2016 Feb.