Pharmacokinetics of Lusutrombopag, a Novel Thrombopoietin Receptor Agonist, in Rats by UPLC-MS/MS.

Bo Wang,Deru Meng,Shuanghu Wang,Changxiong Wang,Liming Hu,Yunfang Zhou,Peiwu Geng,Ailian Hua,Feifei Chen,Quan Zhou,Weiping Ji

doi:10.1155/2020/7290470

Abstract

Lusutrombopag is a second oral thrombopoietin (TPO) receptor agonist that selectively acts on human TPO receptors. In the study, UPLC-MS/MS was used to establish a selective and sensitive method to determine lusutrombopag with poziotinib as IS (internal standard) in rat plasma. Samples were prepared by precipitating protein with acetonitrile as a precipitant. Separation of lusutrombopag and poziotinib was performed on a CORTECS UPLC C18 column (2.1 ∗ 50 mm, 1.6 μm). The mobile phase (acetonitrile and water containing 0.1% formic acid) with gradient elution was set at a flow rate of 0.4 ml/min. The mass spectrometric measurement was conducted under positive ion mode using multiple reaction monitoring (MRM) of m/z 592.97 ⟶ 491.02 for lusutrombopag and m/z for poziotinib (IS) 492.06 ⟶ 354.55. The linear calibration curve of the concentration range was 2–2000 ng/ml for lusutrombopag, with a lower limit of quantification (LLOQ) of 2 ng/ml. RSD of interday and intraday precision were both no more than 9.66% with the accuracy ranging from 105.82% to 108.27%. The extraction recovery of lusutrombopag was between 82.15% and 90.34%. The developed and validated method was perfectly used in the pharmacokinetic study of lusutrombopag after oral administration in rats.

Highlights

Chronic liver disease (CLD) usually includes drug-induced liver disease, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, liver cirrhosis, and liver cancer [1].e incidence of CLD is increasing year by year in China and all over the world
It is usually diagnosed or treated by invasive surgery, but the thrombocytopenia of the disease could significantly increase the risk of bleeding, which hinders the invasive treatment [5, 6]. erefore, efforts are needed to control the occurrence of thrombocytopenia. rombopoietin (TPO) synthesized in the human liver can reduce its occurrence
Lusutrombopag is a second oral TPO receptor agonist that selectively acts on human TPO receptors and activates signaling pathways to produce megakaryocytes through a series of proliferation and differentiation of cells to increase platelet counts [8]

Summary

Introduction

Chronic liver disease (CLD) usually includes drug-induced liver disease, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, liver cirrhosis, and liver cancer [1]. E most common symptom is thrombocytopenia, with up to 76% of patients reporting lower than normal values [3, 4]. It is usually diagnosed or treated by invasive surgery, but the thrombocytopenia of the disease could significantly increase the risk of bleeding, which hinders the invasive treatment [5, 6]. Lusutrombopag is a second oral TPO receptor agonist that selectively acts on human TPO receptors and activates signaling pathways to produce megakaryocytes through a series of proliferation and differentiation of cells to increase platelet counts [8]. The developed and validated method was perfectly used to quantify lusutrombopag in rat plasma and in the pharmacokinetic study of lusutrombopag after oral administration in rats by UPLC-MS/MS

Materials and Methods

Results and Discussion

Conclusions