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Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies.

ABSTRACT: Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double-blind, dose-rising, placebo-controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single-dose study (N = 63) to avatrombopag (1, 3, 10, 20, 50, 75 and 100 mg) or placebo, and in the multiple-dose study (N = 29) to avatrombopag (3, 10 and 20 mg) or placebo daily for 14 days. There were no serious adverse events (AEs), dose-limiting toxicities, deaths, AEs causing withdrawal, thromboses or liver function abnormalities. In both studies, avatrombopag peak concentration and exposure increased proportionally relative to dose; half-life was 18-21 h and independent of dose, supporting once-daily dosing. Effects on platelet counts depended on dose, concentration and treatment duration. Platelet count increases began 3-5 days post-administration, with maximum changes of >370 × 109 /l over baseline with 20 mg daily after 13-16 days. These data support continued development of avatrombopag for treatment of other thrombocytopenic conditions and provide important guidance for the haematologist in the use of this new thrombopoietin receptor agonist.

SUBMITTER: Kuter DJ

PROVIDER: S-EPMC6282597 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies.

Kuter David J DJ Allen Lee F LF

British journal of haematology 20180911 3

Avatrombopag is an oral thrombopoietin receptor agonist that has been recently approved for treating thrombocytopenia in chronic liver disease patients needing invasive procedures. Clinical trials supporting this new treatment were guided by two double-blind, dose-rising, placebo-controlled Phase 1 studies in healthy adults reported here that assessed safety, tolerability and pharmacokinetic profile of avatrombopag, and its effect on platelet counts. Subjects were randomised (2:1) in the single- ...[more]

PMID: 30203841

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Project description:Dietary recommendations for selenium differ between countries, mainly because of uncertainties over the definition of optimal selenium status.The objective was to examine the dose-response relations for different forms of selenium.A randomized, double-blind, placebo-controlled dietary intervention was carried out in 119 healthy men and women aged 50-64 y living in the United Kingdom. Daily placebo or selenium-enriched yeast tablets containing 50, 100, or 200 microg Se ( approximately 60% selenomethionine), selenium-enriched onion meals ( approximately 66% gamma-glutamyl-methylselenocysteine, providing the equivalent of 50 microg Se/d), or unenriched onion meals were consumed for 12 wk. Changes in platelet glutathione peroxidase activity and in plasma selenium and selenoprotein P concentrations were measured.The mean baseline plasma selenium concentration for all subjects was 95.7 +/- 11.5 ng/mL, which increased significantly by 10 wk to steady state concentrations of 118.3 +/- 13.1, 152.0 +/- 24.3, and 177.4 +/- 26.3 ng/mL in those who consumed 50, 100, or 200 microg Se-yeast/d, respectively. Platelet glutathione peroxidase activity did not change significantly in response to either dose or form of selenium. Selenoprotein P increased significantly in all selenium intervention groups from an overall baseline mean of 4.99 +/- 0.80 microg/mL to 6.17 +/- 0.85, 6.73 +/- 1.01, 6.59 +/- 0.64, and 5.72 +/- 0.75 microg/mL in those who consumed 50, 100, or 200 microg Se-yeast/d and 50 microg Se-enriched onions/d, respectively.Plasma selenoprotein P is a useful biomarker of status in populations with relatively low selenium intakes because it responds to different dietary forms of selenium. To optimize the plasma selenoprotein P concentration in this study, 50 microg Se/d was required in addition to the habitual intake of approximately 55 microg/d. In the context of established relations between plasma selenium and risk of cancer and mortality, and recognizing the important functions of selenoprotein P, these results provide important evidence for deriving estimated average requirements for selenium in adults. This trial was registered at clinicaltrials.gov as NCT00279812.

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Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies.

Publications

Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies.

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