Li Ping, Huang Jie, Geng Donghao, Liu Peihua, Chu Zhaoxing, Zou Jianjun, Yang Guoping, Liu Li
Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China.
Front Pharmacol. 2020 Nov 30;11:588286. doi: 10.3389/fphar.2020.588286. eCollection 2020.
HY-021068 [4-(2-(1H-imidazol-1-yl) ethoxy)-3-methoxybenzoate], developed by Hefei Industrial Pharmaceutical Institute Co., Ltd. (Anhui, China), is a potential thromboxane synthetase inhibitor under development as an anti-platelet agent for the treatment of stroke. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize the PK of HY-021068 and its platelet aggregation inhibitory effect in beagle dogs. Beagle dogs received single oral administration of 2.5 mg/kg HY-021068 or consecutively oral administration of 5 mg/kg HY-021068 once daily for 7 days. The plasma concentration of HY-021068 and the platelet aggregation rate (PAR) were determined by liquid chromatography tandem-mass spectrometry (LC-MS/MS) assay and a photometric method, respectively. The PK/PD data was sequentially fitted by Phoenix NLME. The PK/PD parameters of HY-021068 in beagle dogs were estimated by 2.5 and 5 mg/kg dosing on the 1st day, and then used to simulate the PAR of HY-021068 on the 7th day after 5 mg/kg dosing daily. A one-compartment model with saturable Michaelis-Menten elimination was best fitted to the PK of HY-021068. A mechanistic PD model based on irreversible inhibition of thromboxane synthetase was constructed to describe the relationship between plasma concentration of HY-021068 and PAR. Diagnostic plots showed no obvious bias. Visual predictive check confirmed the stability and reliability of the model. Most of PK/PD observed data on the 7th day after 5 mg/kg dosing fell in the 90% prediction interval. We established a semi-mechanistic PK/PD model for characterizing the PK of HY-021068 and its anti-platelet effect in beagle dogs. The model can be used to predict the concentration and PAR under different dosage regimen of HY-021068, and might be served as a reference for dose design in the future clinical studies.
HY-021068[4-(2-(1H-咪唑-1-基)乙氧基)-3-甲氧基苯甲酸酯]由合肥工业大学药物研究所（中国安徽）研发，是一种正在开发的潜在血栓素合成酶抑制剂，作为抗血小板药物用于治疗中风。建立了一个半机制药代动力学/药效学（PK/PD）模型，以表征HY-021068在比格犬体内的药代动力学及其血小板聚集抑制作用。比格犬单次口服2.5mg/kg HY-021068或连续7天每天口服5mg/kg HY-021068。分别采用液相色谱串联质谱（LC-MS/MS）法和光度法测定HY-021068的血浆浓度和血小板聚集率（PAR）。PK/PD数据由Phoenix NLME依次拟合。通过第1天2.5和5mg/kg的给药剂量估算比格犬体内HY-021068的PK/PD参数，然后用于模拟每天口服5mg/kg后第7天HY-021068的PAR。一个具有饱和米氏消除的一室模型最适合HY-021068的药代动力学。构建了一个基于血栓素合成酶不可逆抑制的机制性药效学模型，以描述HY-021068血浆浓度与PAR之间的关系。诊断图显示无明显偏差。可视化预测检查证实了模型的稳定性和可靠性。5mg/kg给药后第7天的大多数PK/PD观察数据落在90%预测区间内。我们建立了一个半机制PK/PD模型，以表征HY-021068在比格犬体内的药代动力学及其抗血小板作用。该模型可用于预测不同给药方案下HY-021068的浓度和PAR，并可能为未来临床研究中的剂量设计提供参考。
