PMID- 31243790
OWN - NLM
STAT- MEDLINE
DCOM- 20200819
LR  - 20200819
IS  - 1552-4604 (Electronic)
IS  - 0091-2700 (Linking)
VI  - 59
IP  - 12
DP  - 2019 Dec
TI  - First-in-Human Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics 
      of an Oral Formulation of DS-1040, an Inhibitor of the Activated Form of 
      Thrombin-Activatable Fibrinolysis Inhibitor, in Healthy Subjects.
PG  - 1669-1677
LID - 10.1002/jcph.1474 [doi]
AB  - DS-1040, a low-molecular-weight imidazole derivative, inhibits the enzymatic 
      activity of thrombin-activatable fibrinolysis inhibitor (TAFIa), enhancing 
      endogenous tissue plasminogen activator-triggered fibrinolysis. This 
      first-in-human, randomized, placebo-controlled, phase 1 study evaluated the 
      safety, pharmacokinetics (PK), and pharmacodynamics (PD) of an oral formulation 
      of DS-1040. Healthy adults (aged 20-45 years; N = 56) were randomized 3:1 to 
      receive DS-1040 orally administered as single ascending doses (50, 100, 200, or 
      400 mg) or placebo, or DS-1040 multiple ascending doses (100 mg once daily, 
      200 mg once daily, or 150 mg twice daily) or placebo for 14 days. Safety, PK, and 
      PD parameters were assessed. All doses of DS-1040 were well tolerated; no 
      serious/severe adverse events (AEs) or discontinuations due to AEs occurred. 
      DS-1040 had no effect on coagulation parameters, and no treatment-related trends 
      in the bleeding time were observed. DS-1040 exposure (peak concentration and area 
      under the concentration-time curve) increased in a dose-proportional manner 
      across the single-dose range. With multiple doses, steady state was achieved by 
      day 7 with minimal accumulation (mean accumulation ratio 1.15-1.25), and the PK 
      was time-independent. After 72 hours, approximately 10% of the DS-1040 400-mg 
      single dose was recovered in urine as intact parent drug. The mean terminal 
      half-life ranged from 17.2 to 24.9 hours, which was similar to previous 
      intravenous administration data. Dose-dependent inhibition of total TAFIa 
      activity was observed following single and multiple doses of oral DS-1040. The 
      safety and PK/PD profiles of oral DS-1040 in healthy subjects support further 
      clinical development.
CI  - (c) 2019, The American College of Clinical Pharmacology.
FAU - Zhou, Jin
AU  - Zhou J
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Limsakun, Tharin
AU  - Limsakun T
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Yin, Ophelia
AU  - Yin O
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Warren, Vance
AU  - Warren V
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Zamora, Cynthia
AU  - Zamora C
AD  - Worldwide Clinical Trials, San Antonio, TX, USA.
FAU - Atiee, George
AU  - Atiee G
AD  - Worldwide Clinical Trials, San Antonio, TX, USA.
FAU - Kochan, Jarema
AU  - Kochan J
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Pav, Joseph
AU  - Pav J
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Kobayashi, Fumiaki
AU  - Kobayashi F
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Vashi, Vijay
AU  - Vashi V
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
FAU - Dishy, Victor
AU  - Dishy V
AD  - Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20190627
PL  - England
TA  - J Clin Pharmacol
JT  - Journal of clinical pharmacology
JID - 0366372
RN  - 0 (Anticoagulants)
RN  - 0 (Imidazoles)
RN  - 7GBN705NH1 (imidazole)
RN  - EC 3.4.17.20 (Carboxypeptidase B2)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
SB  - IM
MH  - Administration, Oral
MH  - Adult
MH  - Anticoagulants/pharmacokinetics/therapeutic use
MH  - Area Under Curve
MH  - Carboxypeptidase B2/*pharmacokinetics/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Imidazoles/pharmacokinetics/therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Tissue Plasminogen Activator/metabolism
MH  - Young Adult
OTO - NOTNLM
OT  - Fibrinolysis
OT  - pharmacodynamics
OT  - pharmacokinetics
OT  - thrombin-activatable fibrinolysis inhibitor
OT  - thrombosis
EDAT- 2019/06/28 06:00
MHDA- 2020/08/20 06:00
CRDT- 2019/06/28 06:00
PHST- 2019/04/05 00:00 [received]
PHST- 2019/06/05 00:00 [accepted]
PHST- 2019/06/28 06:00 [pubmed]
PHST- 2020/08/20 06:00 [medline]
PHST- 2019/06/28 06:00 [entrez]
AID - 10.1002/jcph.1474 [doi]
PST - ppublish
SO  - J Clin Pharmacol. 2019 Dec;59(12):1669-1677. doi: 10.1002/jcph.1474. Epub 2019 
      Jun 27.