087: Simulating (R)-omeprazole & (S)-omeprazole Pharmacokinetics in Obese & Post-bariatric Surgery Patients by Physiologically based Pharmacokinetic Modeling

Statement of Purpose: Omeprazole is frequently prescribed to post-bariatric patients to prevent marginal ulcers after gastric bypass surgery (RYGB). Previous clinical studies have investigated the effect of bariatric surgeries on omeprazole pharmacokinetics, showing reduced plasma exposure from 1 month up to 6 months after surgery. We aimed to optimize drug dosing in gastric bypass patients by means of a physiologically based pharmacokinetic (PBPK) model for (R)-omeprazole and (S)-omeprazole to describe drug disposition in obese/morbidly obese and post-gastric bypass patients.

Description of Methods & Materials: We developed a PBPK model for (R)-omeprazole and (S)-omeprazole in Simcyp v21. The models incorporated enzyme kinetics data for enantioselective metabolism by CYP3A4 and CYP2C19 obtained by retrograde extrapolation, mechanism-based interaction, and competitive inhibition, also accounting for omeprazole metabolites. The model was verified in healthy volunteers using IV and oral administration, single and multiple doses, and special populations, including obese, morbidly obese and post-gastric bypass populations. Healthy, obese and morbidly obese population were available in the simulator. The post-RYGB population accounted for increased gastric pH, reduced gastric volume, reduced gastric transit time, small intestine bypass, reduced gut abundance of CYP3A4 and altered SI motility and transit time.

Data & Results: Simulated (R)- and (S)-omeprazole plasma concentrations captured the observed data in healthy volunteers, with 93% of predicted data within a 2-fold range. The enantioselective metabolism resulted in higher plasma concentrations of (S)-omeprazole than for its antipode, reflecting the observed data. Parameter sensitivity analysis (PSA) showed that gut abundance of CYP3A4, gastric pH, small intestine length, and the delay in the release of bile do not have a major influence on the AUC of both (R)- and (S)-omeprazole. Bypassing 75-100 cm of the proximal small intestine in the gastric bypass surgery does not lead to a major reduction in simulated C_max or AUC of (R)- and (S)-omeprazole. CYP3A4 liver abundance, which exhibits large interpatient variability, had a major impact on the AUC and C_max of (S)-omeprazole, but not for (R)-omeprazole. However, obesity and weight loss do not seem to impact CYP3A4 liver abundance [Wegler et al., 2022]. The 2-fold increase in CYP2C19 liver abundance as in obese patients [Kvitne et al., 2022] results in 1.7- and 2-fold decrease in the AUC of (R)- and (S)-omeprazole, respectively.

Interpretation, Conclusion or Significance: The developed PBPK models for (S)- and (R)-omeprazole provide a comprehensive understating of the enantioselective disposition of omeprazole enantiomers in various populations. (R)- and (S)-omeprazole PBPK models showed that gastric pH, small intestine bypass, and regional gut abundance of CYP3A do not significantly impact drug exposure. CYP2C19 liver abundance plays a substantial impact on the AUC of (S)- and (R)-omeprazole. With the current approach, we can now move towards proposing optimal dosing strategies for post-gastric bypass patients.

Disclosures: The authors have nothing to disclose.