Center of Clinical Pharmacology, The Second Affiliated Hospital of Zhejiang University, School of Medicine, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.
Eur J Drug Metab Pharmacokinet. 2021 May;46(3):427-436. doi: 10.1007/s13318-021-00682-4. Epub 2021 Mar 29.
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.
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, CYP2C83 rs10509681, CYP2C83 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.
Compared with male subjects, female subjects who received a single 25-mg dose of eltrombopag exhibited a significantly increased mean maximum plasma concentration (C) 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).
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.
https://www.Chinadrugtrials.org.cn CTR20190898.
艾曲波帕是首个用于治疗特发性血小板减少性紫癜的口服、小分子、非肽类血小板生成素受体激动剂。本研究旨在调查艾曲波帕在中国健康受试者中的药代动力学特征，并评估性别和遗传多态性对其变异性的影响。
48 名健康受试者单次给予艾曲波帕（25mg）。采用经验证的液相色谱-串联质谱法测定艾曲波帕的血浆浓度，通过血液检测测定血小板计数。采用 Sanger 测序法对 CYP1A2 rs762551、CYP2C83 rs10509681、CYP2C83 rs11572080、UGT1A1 rs887829、UGT1A3 rs3806596 和 BCRP rs2231142 多态性进行基因分型。构建反向传播人工神经网络（BP-ANN）模型，基于生理因素和遗传多态性数据预测药代动力学。
与男性受试者相比，单次给予 25mg 艾曲波帕的女性受试者的平均最大血浆浓度（C）显著升高，表观清除率显著降低。此外，CYP1A2 rs762551 C>A 单核苷酸多态性影响分布和消除。与纯合 AA 携带者相比，C 等位基因携带者的全身暴露增加 30%，表观清除率降低 20%。男性和女性受试者的血小板计数自基线至第 5 天的平均百分比升高分别为 9.38%和 17.06%。BP-ANN 模型具有较高的拟合优度指数和预测浓度与实测浓度之间的良好一致性（R=0.98979）。
在中国健康受试者中，性别和 CYP1A2 rs762551 C>A 与艾曲波帕的药代动力学变异性相关。与给予相同剂量的男性相比，女性表现出更好的血小板升高作用。基于生理因素和遗传多态性数据建立的 BP-ANN 模型有望在药代动力学研究中得到应用。
https://www.Chinadrugtrials.org.cn CTR20190898。
