Semi-Mechanistic Modeling of HY-021068 Based on Irreversible Inhibition of Thromboxane Synthetase

Ping Li; Jie Huang; Donghao Geng; Peihua Liu; Zhaoxing Chu; Jianjun Zou; Guoping Yang; Li Liu

doi:10.3389/fphar.2020.588286

Semi-Mechanistic Modeling of HY-021068 Based on Irreversible Inhibition of Thromboxane Synthetase

Front Pharmacol. 2020 Nov 30:11:588286. doi: 10.3389/fphar.2020.588286. eCollection 2020.

Authors

Ping Li¹, Jie Huang², Donghao Geng¹, Peihua Liu¹, Zhaoxing Chu¹, Jianjun Zou³, Guoping Yang², Li Liu¹

Affiliations

¹ Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
² Center of Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China.
³ Department of Clinical Pharmacology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

Abstract

Background: 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. Method: 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. Result: 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. Conclusion: 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.

Keywords: HY-021068; pharmacokinetic; pharmacokinetic/pharmacodynamic model; platelet aggregation rate; thromboxane A2.