Impact of target-mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura.

Abstract

AIMS\nThe pharmacokinetics (PK) of hetrombopag was found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag.\n\n\nMETHODS\nNon-linear mixed-effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic ITP patients from two phase I studies and one Phase II study. The final model was evaluated via goodness-of-fit plots, visual predictive check, and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study.\n\n\nRESULTS\nThe pharmacokinetic data of hetrombopag was well described by a modified target-mediated drug disposition (TMDD) model with dual sequential first-order absorption. Mean parameter estimates (inter-individual variability) were: CL/F 7.66 L/h (63.5%), Vc /F 30.0 L (77.2%) and Kdeg 0.693/h (87.1%). The pharmacodynamic profile was well described by a five-compartment lifespan model with four-transit and one-platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once-daily hetrombopag would able to achieve an ideal platelet counts level (50-200 × 109 /L).\n\n\nCONCLUSION\nTMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once-daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.