Impact of obesity and roux-en-Y gastric bypass on the pharmacokinetics of (R)- and (S)-omeprazole and intragastric pH

Abstract

This study employed physiologically-based pharmacokinetic-pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non-obese, morbidly obese, and post-gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5-hydroxy-omeprazole]/[omeprazole]. The morbidly obese model accounted for the down-regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)-omeprazole, while hepatic CYP2C19 affected both (R)- and (S)-omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism-based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non-obese, obese, and post-gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post-RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

FIGURE 1

Predicted versus observed plasma concentration of (R)‐ and (S)‐omeprazole after a single IV bolus administration over 60 s of 20 mg of racemic omeprazole in Japanese healthy volunteers. Observed plasma concentrations are presented as mean (dots), and predicted (n = 100) plasma concentrations are presented as mean (lines) and the 5th–95th percentiles range (shaded area).

FIGURE 2

Predicted and observed plasma concentration of (R)‐, (S)‐, and racemic omeprazole after oral solution administration in non‐obese subjects, 20 and 40 mg q.d. Observations are presented as geometric mean (dots), and predicted (n = 100) plasma concentrations are presented as geometric mean (lines) and the 5th–95th percentiles range (shaded area).

FIGURE 3

Effect of weight loss following bariatric surgery on CYP2C19 and CYP3A4 in vivo activity assessed using omeprazole as a sensitive substrate. The metabolic ratios [5‐hydroxy‐omeprazole]/[omeprazole] and [omeprazole sulphone]/[omeprazole], as biomarkers for CYP2C19 and CYP3A4, respectively, were calculated from plasma concentrations 4 h after omeprazole administration in patients submitted to a Roux‐en‐Y gastric bypass (RYGB) were assessed before and after surgery (a). To control the variability of CYP2C19 due to gene variants, subjects were stratified by genotype (b) and predicted phenotype (c) according to CPIC's guidelines for PPIs. *2/*2 n = 2, *1/*2 n = 11, *2/*17 n = 1, *1/*1 n = 8, *1/*17 n = 11, *17/*17 n = 1, total of 34 patients assessed on both phases of the study.

FIGURE 4

Simulated plasma concentration profiles in obese patients before and after undergoing bariatric surgery. Simulations were carried out to match the clinical study design of the observed data on the 7th day after the administration of 20 mg omeprazole b.i.d. in individuals characterized as CYP2C19 normal metabolizers (a). Additionally, simulations were conducted to replicate the 5th day after the administration 20 mg omeprazole q.d. (b) Observations are presented as mean and standard deviations (symbols and bars) or mean (different shapes), and predicted (n = 100) plasma concentrations are presented as mean (lines) and the 5th–95th percentiles range (shaded area).

FIGURE 5

Goodness of fit plot illustrating the model performance. The solid line represents the line of identity, the dotted lines indicate 1.5‐fold deviation; the dashed lines indicate twofold deviation., , , ,

FIGURE 6

Simulated concentration–time profiles (a) and intragastric pH (b) following the administration of 10–80 mg of racemic omeprazole q.d. for 7 days in non‐obese, obese, and post‐RYGB patients. All simulations were carried out in 100 subjects per group. Data presented as mean (straight lines) and 5th–95th percentiles (shaded area). The pH 4 (gray line) was added as a threshold for the assessment of therapeutic success for the prevention or treatment of marginal ulcers.

FIGURE 7

Simulated average intragastric pH (a) and total time of pH >4 (b) for non‐obese, obese, and post‐Roux‐en‐Y gastric bypass (RYGB) patients depending on omeprazole dose, varying from 10 to 80 mg q.d. over 7 days (n = 100 for each group). The mean daily intragastric pH was defined for the small gastric pouch in patients following a Roux‐en‐Y gastric bypass surgery and for the stomach in the other two groups. Data are displayed as the median (●) with the 5th and 95th percentiles (–) of the geometric means. Obese and post‐RYGB patients were compared with non‐obese as a reference for each dose using the Mann–Whitney U test with a 95% confidence level. Significance was set at p‐value <0.05. *p < 0.05; **p < 0.01; ***p < 0.001, ****p < 0.0001.