Abstract
Hetrombopag as the derivative of ethylidene hydrazine carboxamide was recently developed into a novel patented non-peptide thrombopoietin mimetic and thrombopoietin receptor agonist to treat idiopathic thrombocytopenic purpura. To study the pharmacokinetics of hetrombopag, a highly sensitive, rapid and reliable liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed and validated for determination of hetrombopag in rat plasma. After protein precipitation extraction, the chromatography separation of analyte and internal standard named eltrombopag as an marketed analog of hetrombopag was performed on an Synergi Polar-RP column at the flow rate of 0.5 mL/min, and the determination was conducted on an API4000 triple quadrupole mass spectrometry in the multiple reaction monitoring mode using the respective [M+H]+ ions m/z 459.2 → 200.9 for hetrombopag and m/z 443.2 → 229.0 for IS. The lower limit of quantification was established to be 1 ng/mL, and the linear scope of standard curve was 1–1000 ng/mL. Both the precision (RSD%) and accuracy (RE%) were within the acceptable criterion of below 15 %. The validated method was successfully applied to quantify hetrombopag in the rat plasma and investigate the pharmacokinetics.
Highlights
IntroductionIdiopathic thrombocytopenic purpura (ITP) usually indicating the persistently low platelet counts less than 20,000 mm are associated with an increased risk of serious bleeding such as intracranial hemorrhage (Aledort et al 2004)
Idiopathic thrombocytopenic purpura (ITP) involved in anti-platelet antibody mediated platelet destruction and reduced platelet production is a common autoimmune disease in hematology department (Heitink-Pollé et al 2014; Lo and Deane 2014)
Method validation Method validation was performed based on the US Food and Drug Administration (FDA) guideline for industry bioanalytical method validation (FDA 2001) and European Medicines Agency (EMA) guideline (EMA 2009)
Summary
ITP usually indicating the persistently low platelet counts less than 20,000 mm are associated with an increased risk of serious bleeding such as intracranial hemorrhage (Aledort et al 2004). One of the ITP etiology is that there is no enough thrombopoietin to stimulate platelet production (Kuter 2013). Improving the thrombopoietin concentration level will be great benefit of treating ITP Eltrombapag (SB-497115) as thrombopoietin stimulant agent has been approved by FDA and demonstrated that it can significantly increase the platelet counts in relapsed and refractory ITP patients (Bussel et al 2007; Cheng et al 2011). Hetrombopag(SHR8735,(Z)-5-(2-hydroxy-3-(2(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen2-yl)-1H-pyrazol-4(5H)-ylidene)hydrazinyl)phenyl) furan-2-carboxylic acid), the analog of eltrombopag, was developed by Jiangsu Hengrui pharmaceutical company limited as a novel patented thrombopoietin receptor agonist to treat idiopathic thrombocytopenia (Tang et al 2009). Due to its different structural characteristic and corresponding physicochemical properties of the hetrombopag, it remains to be a challenge to develop a sensitive and selective method for determination of the plasma concentration of this
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
