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Ankrom W, Wood HB, Xu J, et al. Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target. Pharmacol Res Perspect. 2016;4(1):e00207doi: 10.1002/prp2.207.
Ankrom, W., Wood, H. B., Xu, J., Geissler, W., Bateman, T., Chatterjee, M. S., Feng, K. I., Metzger, J. M., Strapps, W. R., Tadin-Strapps, M., Seiffert, D., & Andre, P. (2016). Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target. Pharmacology research & perspectives, 4(1), e00207. https://doi.org/10.1002/prp2.207
Ankrom, Wendy, et al. "Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target." Pharmacology research & perspectives vol. 4,1 (2016): e00207. doi: https://doi.org/10.1002/prp2.207
Ankrom W, Wood HB, Xu J, Geissler W, Bateman T, Chatterjee MS, Feng KI, Metzger JM, Strapps WR, Tadin-Strapps M, Seiffert D, Andre P. Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target. Pharmacol Res Perspect. 2016 Jan 15;4(1):e00207. doi: 10.1002/prp2.207. eCollection 2016 Feb. PMID: 26977298; PMCID: PMC4777260.
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Pharmacol Res Perspect. 2016 Jan 15;4(1):e00207. doi: 10.1002/prp2.207. eCollection 2016 Feb.

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target.

Pharmacology research & perspectives

Wendy Ankrom, Harold B Wood, Jiayi Xu, Wayne Geissler, Tom Bateman, Manash S Chatterjee, Kung-I Feng, Joseph M Metzger, Walter R Strapps, Marija Tadin-Strapps, Dietmar Seiffert, Patrick Andre

Affiliations

  1. PPDM Merck & Co., Inc. Rahway New Jersey.
  2. Discovery Chemistry Merck & Co., Inc. Rahway New Jersey.
  3. In Vitro Pharmacology Merck & Co., Inc. Kenilworth New Jersey.
  4. PPDM Merck & Co., Inc. Kenilworth New Jersey.
  5. Discovery Pharmaceutical Sciences Merck & Co., Inc. Rahway New Jersey.
  6. RNA Therapeutics Merck & Co., Inc. West Point Pennsylvania.
  7. Genetics and Pharmacogenomics Merck & Co., Inc. Boston Massachusetts.
  8. Cardiometabolic Disease Merck & Co., Inc. Kenilworth New Jersey.

PMID: 26977298 PMCID: PMC4777260 DOI: 10.1002/prp2.207

Abstract

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.

Keywords: anticoagulation; factor IX; factor IXa; stroke prevention in atrial fibrillation; thrombosis; translational PK/PD.

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