A first-in-human study of DS-1040, an inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor, in healthy subjects

2017 ◽  
Vol 15 (5) ◽  
pp. 961-971 ◽  
Author(s):  
J. Zhou ◽  
J. Kochan ◽  
O. Yin ◽  
V. Warren ◽  
C. Zamora ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Human Study ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

Plasma TAFI Antigen Variations in Healthy Subjects

2000 ◽  
Vol 83 (06) ◽  
pp. 902-905 ◽  
Author(s):  
P. Chetaille ◽  
M. C. Alessi ◽  
D. Kouassi ◽  
P. E. Morange ◽  
I. Juhan-Vague
Keyword(s):  
Healthy Subjects ◽  
Healthy Individuals ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Mean Values ◽  
Black African ◽  
Individual Variations ◽  
Caucasian Men ◽  
Fibrinolysis Inhibitor ◽  
The One ◽  
Physiological Variations

SummaryThe Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. The physiological variations of plasma TAFI antigen are not well known. We studied TAFI antigen values in healthy populations with a commercially available kit from Milan Analytica (Switzerland). Broad range of TAFI antigen values (from 41% to 259%) was found in a population of 249 healthy individuals. Gender as well as pregnancy did not influence mean values of TAFI antigen. There was a positive correlation between TAFI antigen and age in female (r = 0.28; p <0.05) but not in male populations. Mean TAFI antigen value of a black African male group [mean ± SD (range): 87 ± 23 (39-144%)] was significantly lower than the one of age matched Caucasian men [114 ± 34 (52-259%)] (p <0.0001). TAFI antigen values were very stable within individuals, they did not significantly vary on day time or at several months period.Thus, in contrast to large inter-individual variations, TAFI antigen levels are quite stable within individuals.

Favourable safety profile of S62798, a potent TAFIa (activated thrombin-activatable fibrinolysis inhibitor) inhibitor, in first-in-man study in healthy subjects

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
F Petit Dop ◽  
M Latreille ◽  
L Guicherd ◽  
J.C Mertens ◽  
K Claesen ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Subjects ◽  
Clot Lysis ◽  
Funding Source ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Lysis Time ◽  
Favourable Safety ◽  
Favourable Safety Profile ◽  
Fibrinolysis Inhibitor ◽  
Clot Lysis Time

Abstract Background Thromboembolic diseases, such as venous thromboembolic diseases represent a significant public health burden. S62798, a selective and potent inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa), is being developed as a fibrinolysis enhancer for the treatment of thromboembolic diseases, including pulmonary embolism. TAFIa inhibits the fibrinolysis by limiting plasmin generation. Objectives This double-blind, randomised, placebo-controlled first-in-man study was conducted to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of S62798 in healthy subjects. Methods Young male (18–40 years) subjects were randomised 3:1 to single ascending doses of S62798 ranging from 3.2 mg to 320 mg or placebo, administered as an intravenous bolus followed by a 7 hour 2-step infusion (part 1), or to 30 mg or 40 mg or placebo administered as a 1-min bolus (part 2). Follow-up ranged from 6 to 13 days post S62798 administration depending on cohorts. Exclusion criteria included bleeding disorders, recent bleeding, and abnormal blood coagulation parameters. Anticoagulant/antiplatelet treatments were not allowed for 30 days prior to and during the study. Safety was assessed by recording adverse events (AE), physical examination, vital signs, biochemical, haematological and haemostasis parameters (prothrombin time, activated partial thromboplastin time, thrombin clotting time, D-Dimers and fibrinogen). Plasma and urine samples for PK assessment were collected pre-dose and up to day 13 to assess the full PK profile. In part 1, ex vivo TAFIa inhibition (spiking of purified human TAFIa) and in vitro clot lysis time were assessed at pre-dose, during and after infusion. The study was performed in France in accordance with the declaration of Helsinki revised in Fortaleza. EudraCT number: 2016–002108–25. Results A total of 56 subjects were randomized to part 1 and 16 to part 2. Subjects were (mean ± SD) 29.5 ±- 5.7 years old with a BMI of 23.9±2.6 kg/m2 in part 1 and 31.4±5.2 years old with a BMI of 23.9±2.5 kg/m2 in part 2. All doses of S62798 administered as a bolus and infusion or a single bolus were well tolerated, and no serious adverse events or discontinuations resulting from AEs occurred during the study. No effects of S62798 on haemostasis parameters were observed. Cardiac safety assessed by 12-lead 24h Holter ECG showed no relevant abnormalities. Plasma exposure of S62798 increased proportionally with the dose. S62798 inhibits TAFIa activity and decreases clot lysis time (reflecting TAFIa activity inhibition) rapidly and dose-dependently in all treated groups. Conclusions S62798, a potent TAFIa inhibitor, has a favourable safety profile with a linear PK. PD results on TAFIa inhibition and clot lysis assay suggest that S62798 has relevant properties to pursue clinical development as an enhancer of endogenous fibrinolysis for the treatment of thromboembolic diseases Funding Acknowledgement Type of funding source: Private company. Main funding source(s): IRIS

Low levels of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) in chronic liver disease

2001 ◽  
Vol 120 (5) ◽  
pp. A376-A376
Author(s):  
D VANTHIEL ◽  
M GEORGE ◽  
J AMIRAL
Keyword(s):  
Liver Disease ◽  
Chronic Liver Disease ◽  
Chronic Liver ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor ◽  
Low Levels

scholarly journals POS0672 FIRST-IN-HUMAN STUDY OF GS-5718, AN ORAL IRAK-4 INHIBITOR, IN HEALTHY SUBJECTS: PHARMACOKINETICS, SAFETY, TOLERABILITY, AND ASSESSMENT OF EFFECT OF FOOD AND ACID REDUCING AGENTS ON EXPOSURE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 581.1-581
Author(s):  
K. Anderson ◽  
C. H. Hsueh ◽  
O. Gurtovaya ◽  
A. Mathur ◽  
J. Taylor ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Clinical Laboratory ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Dose Range ◽  
Human Study ◽  
Reducing Agents ◽  
Pharmacokinetic Parameters ◽  
Once Daily ◽  
Effect Of Food

Background:GS-5718 is a potent and selective interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor in clinical development for treatment of inflammatory diseases.Objectives:The aim of this first-in-human study was to evaluate the pharmacokinetics, safety, and tolerability of GS-5718; and the effect of food and acid-reducing agents (ARA) on GS-5718 pharmacokinetics in healthy subjects.Methods:This was a blinded, randomized, placebo-controlled, single and multiple (once daily for 10 days) oral dose study. Healthy male and female subjects were enrolled in ascending dose cohorts and randomized to receive GS-5718 (15, 50 or 150 mg) or placebo. GS-5718 was administered fasted in the single ascending dose cohorts, and under fed conditions (standard meal) in the multiple dose cohorts. The effects of a high-fat meal and omeprazole (a representative ARA) on GS-5718 50 mg dose pharmacokinetics were also evaluated. Serial blood samples were collected and GS-5718 pharmacokinetic parameters were characterized. Safety was assessed by review of adverse events (AEs), clinical laboratory tests, and vital signs.Results:A total of 74 subjects (n = 62 GS-5718; n = 12 placebo) enrolled and completed study drug treatments in this study. GS-5718 was generally well tolerated at all evaluated dose levels; AEs were mild in severity and no dose-limiting toxicities, serious AEs, nor clinically relevant electrocardiogram or vital sign abnormalities were observed in subjects administered GS-5718. GS-5718 exposure was approximately dose proportional across the evaluated multiple ascending dose range. GS-5718 showed low-to-moderate pharmacokinetic variability with median half-life of 25 to 33 hours and 1.6 to 2.4- fold accumulation at steady-state, which was achieved by Day 5-7 of dosing. Food had no clinically meaningful impact on GS-5718 exposure (AUC and Cmax) at the 50 mg dose. Co-administration of omeprazole with GS-5718 reduced GS-5718 exposure (AUC and Cmax) by 23% and 43%, respectively, at the 50 mg dose.Conclusion:GS-5718, administered once daily, was well tolerated following single or multiple dosing up to 150 mg. The pharmacokinetic and safety profile of GS-5718 support the further development in inflammatory diseases with once-daily administrations.Disclosure of Interests:Kacey Anderson Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Chia-Hsiang Hsueh Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Oksana Gurtovaya Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Anubhav Mathur Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, James Taylor Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Adrian Serone Shareholder of: Gilead Sciences, Employee of: Gilead Sciences, Ahmed A. Othman Shareholder of: Gilead Sciences, Employee of: Gilead Sciences

scholarly journals Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

2005 ◽  
Vol 175 (10) ◽  
pp. 6764-6771 ◽  
Author(s):  
Rosemarijn Renckens ◽  
Joris J. T. H. Roelofs ◽  
Simone A. J. ter Horst ◽  
Cornelis van ′t Veer ◽  
Stefan R. Havik ◽  
...  
Keyword(s):  
Liver Injury ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

Thrombin activatable fibrinolysis inhibitor and hemostatic changes in patients with type I diabetes mellitus with and without microvascular complications

2003 ◽  
Vol 14 (6) ◽  
pp. 551-556 ◽  
Author(s):  
Jovan P Antovic ◽  
Marianne Yngen ◽  
Claes-Göran Östenson ◽  
Aleksandra Antovic ◽  
Håkan N Wallen ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type I Diabetes ◽  
Microvascular Complications ◽  
Type I Diabetes Mellitus ◽  
Type I ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor
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