scholarly journals Pharmacokinetics, pharmacodynamics and safety assessment of multiple doses of soticlestat in healthy volunteers

2022 ◽  
Author(s):  
Shining Wang ◽  
Grace Chen ◽  
Emilio Merlo Pich ◽  
John Affinito ◽  
Michael Cwik ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Safety Assessment ◽  
Multiple Doses

scholarly journals Safety, Tolerability, and Pharmacokinetic Properties of Intravenous Delafloxacin After Single and Multiple Doses in Healthy Volunteers

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pp. 53-65 ◽  
Author(s):  
Randall Hoover ◽  
Thomas Hunt ◽  
Michael Benedict ◽  
Susan K. Paulson ◽  
Laura Lawrence ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Single And Multiple Doses ◽  
Multiple Doses ◽  
Pharmacokinetic Properties

Effects of Multiple Doses of Ambrisentan on the Pharmacokinetics of a Single Dose of Digoxin in Healthy Volunteers

2011 ◽  
Vol 51 (1) ◽  
pp. 102-106 ◽  
Author(s):  
Duncan B. Richards ◽  
Rebecca Spence ◽  
Arun Mandagere ◽  
Linda S. Henderson ◽  
Mindy H. Magee
Keyword(s):  
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Effect of Multiple Doses of Montelukast, a CysLT1Receptor Antagonist, on Digoxin Pharmacokinetics in Healthy Volunteers

1999 ◽  
Vol 39 (9) ◽  
pp. 941-944 ◽  
Author(s):  
Marleen Depré ◽  
Anne van Hecken ◽  
René Verbesselt ◽  
Katleen Wynants ◽  
Inge De Lepeleire ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Multiple Doses ◽  
Digoxin Pharmacokinetics

scholarly journals Brain target occupancy of LY3372689, an inhibitor of the O‐GlcNAcase (OGA) enzyme, following administration of single and multiple doses to healthy volunteers

2021 ◽  
Vol 17 (S9) ◽  
Author(s):  
William Kielbasa ◽  
Sergey Shcherbinin ◽  
Paul Goldsmith ◽  
Krista M Phipps ◽  
Kevin Biglan ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Single And Multiple Doses ◽  
Multiple Doses ◽  
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1998 ◽  
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pp. 523-529 ◽  
Author(s):  
BTJ van den Berg ◽  
RT Louwerse ◽  
GJHM Luiken ◽  
RE Jonkers ◽  
CJ van Boxtel
Keyword(s):  
Healthy Volunteers ◽  
Single And Multiple Doses ◽  
Multiple Doses

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Doses of AG-519, an Allosteric Activator of Pyruvate Kinase-R, in Healthy Subjects

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1264-1264
Author(s):  
Ann J Barbier ◽  
Susan Bodie ◽  
Gary Connor ◽  
Elizabeth Merica ◽  
Charles Kung ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Healthy Volunteers ◽  
Pyruvate Kinase ◽  
Small Molecule ◽  
Healthy Subjects ◽  
Employment Equity ◽  
Multiple Doses ◽  
Equity Ownership ◽  
Dose Dependent ◽  
2,3 Dpg

Abstract BACKGROUND Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by deficiency of the glycolytic enzyme red cell PK (PK-R) due to mutations in the PKLR gene. PK catalyzes the last enzymatic step in the glycolytic pathway and is the main source of adenosine triphosphate (ATP) production in red blood cells. PKLR mutations lead to defective proteins that are hypothesized to reduce ATP levels in red cells, leading to hemolysis. Small molecule allosteric activation of PK-R resulting in increases in ATP and decreases in 2,3-diphosphoglycerate (2,3-DPG) in healthy volunteers has been observed with an earlier molecule, AG-348, the first small molecule PK-R activator to enter clinical trials (Yang et al. EHA 2015, S138). AG-519 is the second small molecule PK-R activator to enter clinical trials. AG-519 is a potent, highly selective and orally bioavailable PK-R activator devoid of the aromatase inhibitory effects that were observed with AG-348. AIMS AG-519 is currently being tested in a randomized, double-blind, phase 1 study in healthy volunteers (NCT02630927), with the objective of identifying a safe and pharmacodynamically active dose and schedule to support potential ongoing development in patients with PK deficiency. Here we report the first 4 cohorts of the multiple ascending dose (MAD) phase of this study. The single ascending dose (SAD) phase of the study and the first two cohorts of the MAD phase of the study have been reported previously (Barbier et al. EHA 2016, P752). METHODS Healthymen and women (non-childbearing potential) aged 18-60 years who provided informed consent were eligible. The MAD phase of the study consisted of 5 dose cohorts. The dose levels administered were determined during interim data reviews of each completed MAD cohort, as well as data from completed SAD cohorts. At each dose level, 8 subjects were enrolled and randomized to receive AG-519 (n=6) or placebo (n=2) twice daily (BID; approximately every 12 hours) for 14 days. Safety assessments included adverse events (AEs), vital signs, electrocardiogram and clinical laboratory parameters. Serial blood samples were drawn to measure plasma concentrations of AG-519 and whole blood concentrations of 2,3-DPG and ATP for pharmacokinetic and pharmacodynamic (PD) assessments. RESULTS Data are available for 32 subjects enrolled across 4 dose cohorts in the MAD phase of the study: 8 subjects each in cohort 1 (125 mg BID), cohort 2 (375 mg BID), cohort 3 (25 mg BID), and cohort 4 (300 mg BID). Blinded safety reviews indicated that multiple doses up to 375 mg have been well tolerated with no serious AEs or dose-limiting toxicities reported to date. One case of probable drug-induced Grade 2 thrombocytopenia was previously reported in 1 subject in the 375 mg cohort; the event was rapidly reversible with no clinical sequelae. The protocol was amended to require daily monitoring of platelets in subsequent cohorts and no other subjects have developed thrombocytopenia during treatment. The preliminary analysis of free testosterone and estradiol confirmed the absence of aromatase inhibitory activity. AG-519 steady-state was reached the third day after the first dose based on trough concentration values. The clearance of AG-519 after multiple doses was similar to that observed after single doses in the SAD cohorts. Dose-dependent increases in ATP in blood (Figure 1) and decreases in 2,3-DPG in blood correlated with dose-dependent increases in exposure of AG-519, with a peak effect at or below 375 mg BID. ATP response at 25 mg appears to be greater than 50% of maximal response. Results from the fifth MAD cohort, which evaluated the PD results with 10 mg BID, will be presented. ATP = adenosine triphosphate; BID = twice daily CONCLUSION AG-519 is well tolerated in healthy subjects at doses ranging from 25 mg to 375 mg BID for 14 days. The robust dose-dependent changes in ATP and 2,3-DPG concentrations in blood from healthy volunteers are consistent with increased activity of PK-R, the expected PD effect of AG-519. These data support the hypothesis that AG-519 may be able to enhance glycolytic activity in red cells of patients with PK deficiency to address the underlying cause of the disease. Figure 1 Change of ATP concentration in blood from baseline Figure 1. Change of ATP concentration in blood from baseline Disclosures Barbier: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bodie:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Connor:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Merica:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kung:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Le:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yang:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kosinski:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Silverman:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yuan:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Bowden:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cohen:Agios Pharmaceuticals, Inc.: Consultancy.

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