Physiologically based pharmacokinetic-pharmacodynamic modeling for prediction of vonoprazan pharmacokinetics and its inhibition on gastric acid secretion following intravenous/oral administration to rats, dogs and humans

摘要

Vonoprazan is characterized as having a long-lasting antisecretory effect on gastric acid.In this study we developed a physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model linking to stomach to simultaneously predict vonoprazan pharmacokinetics and its antisecretory effects following administration to rats,dogs,and humans based on in vitro parameters.The vonoprazan disposition in the stomach was illustrated using a limited-membrane model.In vitro metabolic and transport parameters were derived from hepatic microsomes and Caco-2 cells,respectively.We found the most predicted plasma concentrations and pharmacokinetic parameters of vonoprazan in rats,dogs and humans were within-twofold errors of the observed data.Free vonoprazan concentrations (fu × C2) in the stomach were simulated and linked to the antisecretory effects of the drug (Ⅰ) (increases in pH or acid output) using the fomula dl/dt =k × fu × C2 × (Imax-(η))-kd × I.The vonoprazan dissociation rate constant kd (0.00246 min-1) and inhibition index K1 (35 nM) for H+/K+-ATPase were obtained from literatures.The vonoprazan-H+/K+-ATPase binding rate constant k was 0.07028 min-1· μM-1 using ratio of kd to K1.The predicted antisecretory effects were consistent with the observations following intravenous administration to rats (0.7 and 1.0 mg/kg),oral administration to dogs (0.3 and 1.0 mg/kg) and oral single dose or multidose to humans (20,30,and 40 mg).Simulations showed that vonoprazan concentrations in stomach were 1000-fold higher than those in the plasma at 24 h following administration to human.Vonoprazan pharmacokinetics and its antisecretory effects may be predicted from in vitro data using the PBPK-PD model of the stomach.These findings may highlight 24-h antisecretory effects of vonoprazan in humans following single-dose or the sustained inhibition throughout each 24-h dosing interval during multidose administration.