Jinliang Chen1, Yichao Xu1, Honggang Lou1, Bo Jiang1, Rong Shao1, Dandan Yang1, Yin Hu1, Zourong Ruan2. 1. Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. 2. Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China. zrlcyl@zju.edu.cn.
Abstract
BACKGROUND AND OBJECTIVE: Eltrombopag is the first oral, small-molecule, non-peptide thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. This study investigated the pharmacokinetics of eltrombopag in healthy Chinese subjects and evaluated the effect of sex and genetic polymorphisms on its variability. METHODS: Forty-eight healthy subjects were administered a single dose of eltrombopag (25 mg). Plasma concentrations of eltrombopag were determined using a validated liquid chromatography-tandem mass spectrometry method, and platelet counts were determined by blood tests. CYP1A2 rs762551, CYP2C8*3 rs10509681, CYP2C8*3 rs11572080, UGT1A1 rs887829, UGT1A3 rs3806596, and BCRP rs2231142 polymorphisms were genotyped by Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was constructed to predict pharmacokinetics based on physiological factors and genetic polymorphism data. RESULTS: Compared with male subjects, female subjects who received a single 25-mg dose of eltrombopag exhibited a significantly increased mean maximum plasma concentration (Cmax) and significantly decreased apparent clearance. Additionally, CYP1A2 rs762551 C>A single nucleotide polymorphism influenced distribution and elimination. C-allele carriers exhibited 30% higher systemic exposure and 20% lower apparent clearance compared with homozygous A-allele carriers. Mean percentage increases in platelet counts from baseline to Day 5 were 9.38% and 17.06% in male and female subjects, respectively. The BP-ANN model had a high goodness-of-fit index and good coherence between predicted and measured concentrations (R = 0.98979). CONCLUSION: Sex and CYP1A2 rs762551 C>A were associated with the pharmacokinetic variability of eltrombopag in healthy Chinese subjects. Females exhibited a better platelet-elevating effect compared with males administered the same dosage. The developed BP-ANN model based on physiological factors and genetic polymorphism data could be promising for applications in pharmacokinetic studies. TRIAL REGISTRATIONS: https://www.Chinadrugtrials.org.cn CTR20190898.
BACKGROUND AND OBJECTIVE:Eltrombopag is the first oral, small-molecule, non-peptide thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. This study investigated the pharmacokinetics of eltrombopag in healthy Chinese subjects and evaluated the effect of sex and genetic polymorphisms on its variability. METHODS: Forty-eight healthy subjects were administered a single dose of eltrombopag (25 mg). Plasma concentrations of eltrombopag were determined using a validated liquid chromatography-tandem mass spectrometry method, and platelet counts were determined by blood tests. CYP1A2rs762551, CYP2C8*3 rs10509681, CYP2C8*3 rs11572080, UGT1A1rs887829, UGT1A3rs3806596, and BCRPrs2231142 polymorphisms were genotyped by Sanger sequencing. A back-propagation artificial neural network (BP-ANN) model was constructed to predict pharmacokinetics based on physiological factors and genetic polymorphism data. RESULTS: Compared with male subjects, female subjects who received a single 25-mg dose of eltrombopag exhibited a significantly increased mean maximum plasma concentration (Cmax) and significantly decreased apparent clearance. Additionally, CYP1A2rs762551 C>A single nucleotide polymorphism influenced distribution and elimination. C-allele carriers exhibited 30% higher systemic exposure and 20% lower apparent clearance compared with homozygous A-allele carriers. Mean percentage increases in platelet counts from baseline to Day 5 were 9.38% and 17.06% in male and female subjects, respectively. The BP-ANN model had a high goodness-of-fit index and good coherence between predicted and measured concentrations (R = 0.98979). CONCLUSION: Sex and CYP1A2rs762551 C>A were associated with the pharmacokinetic variability of eltrombopag in healthy Chinese subjects. Females exhibited a better platelet-elevating effect compared with males administered the same dosage. The developed BP-ANN model based on physiological factors and genetic polymorphism data could be promising for applications in pharmacokinetic studies. TRIAL REGISTRATIONS: https://www.Chinadrugtrials.org.cn CTR20190898.
Authors: Francesco Rodeghiero; Roberto Stasi; Terry Gernsheimer; Marc Michel; Drew Provan; Donald M Arnold; James B Bussel; Douglas B Cines; Beng H Chong; Nichola Cooper; Bertrand Godeau; Klaus Lechner; Maria Gabriella Mazzucconi; Robert McMillan; Miguel A Sanz; Paul Imbach; Victor Blanchette; Thomas Kühne; Marco Ruggeri; James N George Journal: Blood Date: 2008-11-12 Impact factor: 22.113
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