Population Pharmacokinetic/Pharmacodynamic Analysis of HHT120, a Novel Direct Thrombin Inhibitor, in Healthy Participants from a Phase I Clinical Trial.

INTRODUCTION

HHT120 is a novel orally administrable direct thrombin inhibitor. In this study, the pharmacokinetic (PK) profiles of HHT120 and its active metabolite Rn-001 were investigated in a first-in-human study and further analyzed with modeling approaches.

METHODS

Population pharmacokinetic (PopPK) model and pharmacokinetic/pharmacodynamic (PK/PD) model were developed to describe the dose-exposure-response relationship after HHT120 administration. Furthermore, the activated partial thromboplastin time (APTT) under different dosing regimens was performed to evaluate the anticoagulant effect.

RESULTS

In total, 74 healthy participants were involved in the dataset involving single ascending dose (SAD), multiple ascending dose (MAD) as well as food effect (FE) phases, and 918 observations of HHT120 concentration as well as 1697 observations of Rn-001 were collected. A total number of 1314 APTT observations were obtained from 62 subjects excluding FE phase. An Erlang model with 7 transit compartments was utilized in the PopPK model to capture the production of Rn-001, and a three-compartment model was employed to describe the disposition. Covariates were screened on the PK parameters in a stepwise style, and no significant covariate effect was found in the current model. Besides, the relationship of plasma concentration of Rn-001 and APTT was characterized by a direct effect with a mixture of linear and nonlinear models. Simulations showed that HHT120 administered once daily at 100-300 mg or twice daily at 100-200 mg led to an increase of APTT within 2-fold of the upper limit, suggesting good safety profiles of HHT120 in the simulated dose regimens.

CONCLUSIONS

The PopPK/PD model offers evidence for the efficacy and safety properties of HHT120 and are expected to provide valuable insights for subsequent clinical research and development of HHT120.

TRIAL REGISTRATION: China Drug Trials Registry ( https://www.chinadrugtrials.org.cn ) identifier no. CTR20221837.