Pharmacokinetics,Pharmacodynamics And Food Effects Of Single And Multiple Doses Of HY-021068 In Healthy Chinese Subjects

Objectives:HY-021068 is a kind of novel thromboxane synthase inhibitor,intended for thromboembolic diseases such as ischemic stroke.This study aimed to assess the pharmacokinetics,pharmacodynamics,safety and tolerability of HY-021068 and food effects on it,in healthy Chinese subjects.Methods:（1）A randomized,double-blind,positive drug-controlled（aspirin）and placebo-controlled,dose-escalation trial was conducted to evaluate the safety,tolerability and pharmacokinetics of HY-021068 in healthy Chinese subjects after single dose administration.The single dose groups were 30 mg,60 mg,115 mg,180 mg,245 mg,300 mg,and 375mg,with a total of 7 dose groups.Through the analysis of the results of the single dose trail,the appropriate dosage of the multiple doses trail can be determined to be 300 mg Qd and 300 mg Bid.A randomized,open-label,two-period,cross-over trial was conducted to evaluate the food effects on the pharmacokinetics and safety of HY-021068.（2）The pharmacokinetic blood sampling time points were:0h,5min,10min,20min,30min,45min,1h,1.5h,2h,3h,4h,6h,8h,10h,12h,24h,36h,48h,72h.The plasma concentrations were detected by LC-MS/MS method,and the pharmacokinetic parameters were calculated by using Phoenix^TMWin Nonlin^?8.1 software.（3）The pharmacodynamic blood sampling time points were:0h,1h,1.5h,2h,4h,8h,12h,24h.Using the PL-12 platelet function analyzer to determine the platelet inhibition rate（IPA）,then analyze the pharmacodynamics of HY-021068 in Chinese healthy subjects after single-dose or multiple-dose administration,and food effects on it.The correlation between IPA and plasma concentration,the maximum value of IPA and drug exposure was analyzed,and a preliminary exposure-response relationship assessment was carried out.Results:（1）In single dose trail,HY-021068 exhibited linear pharmacokinetic characteristics in healthy subjects,showed no gender difference,and the dose escalation reached a plateau at the 375 mg.In multiple doses trial,HY-021068 showed slight accumulation at 300 mg Qd and 300 mg Bid.The adverse reactions in the single dose trail and multiple dose trial were mild,HY-021068 was well tolerated.（2）Under fasting and fed condition,the absorption of HY-021068under fed condition was delayed and the exposure was decreased,which was manifested as an increase in T_maxand a decrease in C_max,AUC_0-tand AUC_0-∞.The adverse reactions were mild,and there was no significant difference during the two-period trail.（3）In the single dose trail,the maximum value of IPA basically increased with the increase of the dose.When the dose increased to375mg,there was no statistical difference with the previous dose group of300mg,and no statistical difference with 100mg aspirin.In the multiple dose trail,when HY-021068 was administered at doses of 300 mg Qd and300 mg Bid,it could reach the similar maximum level of IPA with 100mg aspirin.Compared with aspirin,HY-021068 has a faster onset of action,but its inhibitory effect on platelet aggregation is shorter than aspirin.When the plasma concentration and exposure of HY-021068 were in the lower range,there was a certain positive correlation trend with IPA and the maximum value of IPA.With the increase of plasma concentration and exposure,the drug effect gradually approached saturation.Conclusion:HY-021068 showed good safety and tolerability in Chinese healthy subjects,exhibits linear pharmacokinetic characteristics.HY-021068 has a faster onset,and the exposure-response has a positive correlation trend.This first-in-human study supports the further development of HY-021068 in phase II clinical trails.