Exploring Differences in Pharmacometrics of Rabeprazole between Genders via Population Pharmacokinetic-Pharmacodynamic Modeling

Abstract

Rabeprazole is a proton pump inhibitor that inhibits gastric acid production and increases gastric pH; it is widely used clinically as a treatment option for gastritis and gastric ulcers. However, information on the inter-individual variability of rabeprazole pharmacometrics, which is a key element in establishing its scientific clinical use, is still lacking. Particularly, the differences in pharmacokinetics between genders and the degree of variation in pharmacodynamics have not been clearly identified. Thus, the main purpose of this study was to explore any differences in rabeprazole pharmacokinetics between genders and to quantitatively predict and compare the effects of any differences in pharmacokinetics between genders on known pharmacodynamics using population pharmacokinetic-pharmacodynamic modeling. To compare pharmacokinetics and modeling data between genders, bioequivalence results were used simultaneously on healthy Korean men and women using the physiological and biochemical parameters derived from each individual. Pharmacodynamic modeling was performed based on the data of previously reported gastric pH changes in response to rabeprazole plasma concentrations, which was co-linked to the central compartmental bioavailable concentration in the population pharmacokinetic model. There was no significant difference in the level of rabeprazole exposure and elimination of plasma between genders following oral administration of 10 mg enteric-coated rabeprazole tablets; however, there was a clear delay in absorption in women compared to men. Additionally, a comparison of pharmacokinetic parameters normalized to body weight between genders showed that the maximum plasma concentrations were significantly higher in women than in men, again suggesting gender differences in rabeprazole absorption. The population pharmacokinetic profiles for rabeprazole were described using a three-sequential multi-absorption with lag time (T_lag) two-compartment model, whereas body surface area and gender were explored as effective covariates for absorption rate constant and T_lag, respectively. The effect of increased gastric pH due to plasma exposure to rabeprazole was explained using the Sigmoid Emax model, with the baseline as a direct response. The significantly longer rabeprazole T_lag in females delayed the onset of an effect by an average of 1.58 times (2.02-3.20 h), yet the overall and maximum effects did not cause a significant difference within 15%. In the relative comparison of the overall efficacy of rabeprazole enteric-coated tablet administration between genders, it was predicted based on the model that males would have higher efficacy. This study will be very useful in broadening the perspective of interpreting drug diversity between individuals and narrowing the gap in knowledge related to scientific precision medicine by presenting new information on gender differences in rabeprazole pharmacometrics that had not been previously identified.

Keywords: absorption phase; gastric pH; gender differences; pharmacodynamics; population pharmacokinetic modeling; rabeprazole.

Figure 1

Plasma concentration profiles before (A–C) and after (D–F) body weight normalization between genders (B,E: male; C,F: female) following oral administration of rabeprazole 10 mg enteric-coated tablets. In graphs (A,D), observations are presented as mean and standard deviation as dots and upward vertical bars, respectively. (B,C,E,F) represent boxplots of plasma concentration values after rabeprazole exposure by time point, and the blue shading in the graph represents the initial absorption phase area from 0 to 2 h after exposure (established to check absorption differences between genders after exposure).

Figure 2

Heatmap results ((A) both males and females; (B) males; (C) females) analyzing the correlation between pharmacokinetic parameter values according to oral administration of 10 mg rabeprazole enteric-coated tablet and biochemical parameters of each individual. Yellow boxes displayed in the heatmap indicate the detection of factors that can reasonably explain the correlation between physiological and biochemical parameters and pharmacokinetic parameters with an absolute correlation coefficient (r) of 0.3 or higher. BMI: body mass index; WBC: white blood cell count; RBC: red blood cell count; Hb: hemoglobin; HT: hematocrit; SNeu: Seg-neutrophils; Lympho: lymphocytes; Eosino: eosinophils; ANC: absolute neutrophil count; BUN: blood–urea–nitrogen; Cr: creatinine; eGFR: estimated glomerular filtration rate; Ptn: total protein; ALP: alkaline phosphatase; AST: aspartate transaminase; ALT: alanine transaminase; GTP: gamma-glutamyl transpeptidase; Bili: total bilirubin; Glc: glucose; Chol: total cholesterol; BSA: body surface area; CrCL: creatinine clearance; T_1/2: half-life; C_max: maximum plasma concentration; T_max: time to reach C_max; AUC_all: area under the curve from 0 to observed (t) time after administration; AUC_inf: area under the curve from 0 to infinity time after administration; V_d: volume of distribution; CL: clearance; F: oral bioavailability; T_lag: lag time in absorption; MRT: mean residence time.

Figure 3

Boxplot results comparing differences in body surface area (BSA) between genders and showing significant correlations with pharmacokinetic parameters identified in the heatmap. * p < 0.05 between male parameter values.

Figure 4

Population pharmacokinetic modeling visual predictive check (VPC) results of observed plasma concentrations following oral administration of 10 mg rabeprazole enteric-coated tablets. Model VPC results are presented separately for the total (A), without stratification, and for males (B) and females (C), separately and stratified by gender. Observed concentrations are depicted by the dots. The 95th, 50th, and 5th percentiles of the predicted concentrations are represented by black dashed lines. The 95% confidence intervals (CIs) for the predicted 5th and 95th percentiles are represented by the blue-shaded regions. The 95% CIs for the predicted 50th percentiles are represented by the red-shaded regions.

Figure 5

Model fitting result (by applying sigmoid E_max model with baseline) of gastric pH values according to rabeprazole plasma concentration. Observed values digitized from the report by Chen et al. (2006) [32] are depicted by the dots. The red line represents the mean values predicted by the model. The dark and light red bands represent the 95% confidence interval and the prediction interval, respectively.

Figure 6

Model prediction results of the gastric pH profiles over time after a single oral exposure to a 10 mg rabeprazole enteric-coated tablet. Prediction results were presented separately for total (A) without stratification and for males (B) and females (C), separately and stratified by gender. The 50th percentiles of the predicted pH values are represented by black dashed lines and the 95% confidence intervals for the predicted 50th percentiles are represented by the red-shaded regions. The green dotted lines in the graph represent the reference value for 4, the pH rise point established as the effective treatment effect of rabeprazole.