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

Abstract

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 (f_u × 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 dI/dt = k × f_u × C₂ × (I_max - I) - k_d × I. The vonoprazan dissociation rate constant k_d (0.00246 min^-1) and inhibition index K_I (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 k_d to K_I. 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.

Keywords: gastric acid secretion; pharmacodynamics; pharmacokinetics; physiologically based pharmacokinetic–pharmacodynamic model; potassium-competitive acid blocker; vonoprazan.

Fig. 1

Schematic structure of the whole-body PBPK-PD for predicting the pharmacokinetic behaviors of vonoprazan and its inhibition of gastric acid secretion following intravenous or oral administration to rats, dogs, and humans. The antisecretory effect of vonoprazan on gastric acid is linked to the stomach. ROB and Q represent the rest of the body and the blood flow rate, respectively

Fig. 2

The predicted results in rats. The predicted (lines) and observed (points) vonoprazan concentration in the plasma of rats following intravenous dose (a 0.5, 1.0, 2.0 mg/kg, n = 5), oral dose (b 2.0 mg/kg, n = 5), and multidose (c 1.0 mg/kg for 7 days, n = 5) administration. d The relationship between the mean observed and predicted concentrations of vonoprazan in the plasma of rats. The solid and dashed lines indicate unity and twofold errors between predicted and observed data, respectively. e The simulated concentration of vonoprazan in the stomach of rats following intravenous administration at 0.5, 0.7, and 1.0 mg/kg, respectively. f The predicted increases (lines) in gastric pH and the observations (points) following administration of the corresponding doses of vonoprazan. g The relationship between the observed and predicted pH levels of the stomach. The solid and dashed lines indicate unity and 1.5-fold errors between predicted and observed data, respectively. The observations were obtained from the literature [12] and were induced by intravenous infusions of histamine

Fig. 3

The results of tissue distribution in rats. The predicted (lines) and observed (points) vonoprazan concentrations in the heart (a), liver (b), spleen (c), lungs (d), stomach (e), intestines (f), muscle (g), brain (h), kidneys (i), adipose (j), and skin (k) of rats following intravenous administration of 1 mg/kg vonoprazan (n = 5). l The relationship between the mean observed and predicted concentrations of vonoprazan in the tissues. The solid and dashed lines indicate unity and twofold errors between predicted and observed data, respectively

Fig. 4

The predicted results in dogs. The predicted (lines) and observed (points) vonoprazan concentration in the plasma of dogs following intravenous single-dose administration (a 0.15, 0.3, 0.6 mg/kg, n = 8), oral administration (b 0.6 mg/kg, n = 8), and multidose administration (c 0.3 mg/kg for 7 days, n = 8). d The relationship between the mean observed and predicted vonoprazan concentrations in the plasma of dogs. The solid and dashed lines indicate unity and twofold errors between predicted and observed data, respectively. e The predicted vonoprazan concentration in the stomach of dogs following oral administration of 0.1, 0.3, and 1.0 mg/kg vonoprazan. f The predicted (lines) and observed (points) output of gastric acid (% of predose levels) following oral administration of vonoprazan to dogs. g The relationship between the observed and predicted outputs of gastric acid (% of predose levels) in the stomach. The solid and dashed lines indicate unity and twofold errors between predicted and observed data, respectively. The observations of gastric acid output were cited from the literature [30] in the Heidenhain pouches of dogs induced by subcutaneous infusions of histamine

Fig. 5

The predicted results in humans. The predicted (lines) and observed (points) vonoprazan concentrations in the plasma of humans following oral single-dose (a 5, 10, 20, and 40 mg) and multidose administration (b 10, 20, 30, and 40 mg for 7 days). The observed data were cited in the literature [5, 14] in Japanese. c The relationship between the mean observed and predicted plasma concentrations of vonoprazan in humans. The solid and dashed lines indicate unity and twofold errors between predicted and observed data, respectively. d The predicted vonoprazan concentrations in the stomach of humans following oral single-dose and multidose administration of 10, 20, 30, and 40 mg vonoprazan. e The predicted (lines) and observed (points) pH values following oral single-dose or multidose administration of 10, 20, 30, and 40 mg vonoprazan to humans. The observations were cited from literature [14] from Japan and the UK. f The relationship between the observed and predicted alterations in pH in the stomach of humans. The solid and dashed lines indicate unity and 1.5-fold errors between predicted and observed data, respectively. g Visual predictive checks of the predicted concentrations of vonoprazan following oral single-dose or multidose administration of 20 mg vonoprazan to humans. The observed data were cited from the literature [5, 14, 28]. h Visual predictive checks of the predicted alterations in gastric pH following oral single-dose or multidose administration of 20 mg vonoprazan to humans. Solid lines represent the 50th percentiles. Dashed lines represent the 5th and 95th percentiles of the simulated populations. Points represent observed data cited from the literature [5, 14, 15, 29]