Effect Of Obesity And Laparoscopic Sleeve Gastrectomy On Omeprazole Pharmacokinetics Using Population Pharmacokinetics Model

Background and ObjectiveObese patients usually suffer from type 2 diabetes,hypertension,dyslipidemia,sleep apnea syndrome,osteoarthritis and other diseases,therefore,they often require medical or surgical treatment.Laparoscopic sleeve gastrectomy is currently the most performed weight loss surgery in the world,which could help obese patients achieve sustained weight loss and improve related complications.As a first-generation proton pump inhibitor,omeprazole has been widely used for the maintenance treatment of gastroesophageal reflux disease in obese patients,as well as the relief of gastrointestinal discomfort and the prevention of gastric ulcer after bariatric surgery.However,pharmacokinetic characteristics and dose recommendations for omeprazole in obese patients and patients undergoing sleeve gastrectomy are lacking at present.Therefore,this study aims to investigate the effect of obesity and sleeve gastrectomy on the pharmacokinetics of omeprazole,meanwhile,it is expected to further understand the pathophysiological alterations in obese patients and patients undergoing laparoscopic sleeve gastrectomy,and to provide reference for the rational use of other drugs.Methods(1)Data on obese patients admitted to the Bariatric and Metabolic Surgery Unit of the Third Xiangya Hospital of Central South University were prospectively collected from May 2021 to November 2021.Based on the designed sampling scheme,blood samples were collected after a single oral administration of 20 mg omeprazole enteric-coated capsules before surgery and after laparoscopic sleeve gastrectomy,and the plasma concentrations was measured by high performance liquid chromatographytandem mass spectrometry.At the same time,demographic characteristics,liver and kidney function,dosing time and other relevant data were recorded.(2)Omepraozle plasma concentrations and related covariates data in normal-weight volunteers were obtained from Research Center for Clinical Trials of the Third Xiangya Hospital of Central South University,and then used NONMEM software to establish a population pharmacokinetics model of omeprazole in normal-weight and obese individuals and a population pharmacokinetics model of omeprazole before surgery and after sleeve gastrectomy in obese patients,and evaluated the effects of covariates such as body weight,sleeve gastrectomy,and CYP2C19 genotype on the pharmacokinetics of omeprazole,respectively.Finally,based on Monte carlo simulations,the appropriate oral dose of omeprazole was recommended for obese patients and patients undergoing sleeve gastrectomy.Results(1)Based on the omeprazole plasma concentrations data in 40 normalweight volunteers and 61 obese patients,a population pharmacokinetic model for omeprazole in a wide body weight range(48 kg-203 kg)was developed,and a one-compartment model with twelve transit absorption compartments and linear elimination described the data best.CYP2C19 genotype was identified as a covariate that significantly affected clearance.In addition,obese patients showed a lower clearance of omeprazole compared to normal-weight volunteers,possibly due to reduced activity of the CYP2C19 metabolizing enzyme in obese patients.The simulation results showed that the exposure of healthy volunteers taking 40 mg omeprazole was comparable to that of obese patients with normal liver function who took 20 mg omeprazole,and comparable to that of obese patients with mild liver dysfunction who took 10 mg omeprazole.(2)Based on the concentrations data of omeprazole in 61 obese patients and 40 patients undergoing sleeve gastrectomy,a population pharmacokinetic model of omeprazole was constructed,and the final model was a one-compartment model with twelve transit absorption compartments and linear elimination.Compared with baseline values,the mean transit time of omeprazole was significantly shortened on the 7th day after surgery,indicating that the postoperative absorption rate was accelerated.But no changes in clearance was observed,demonstrating that there were no differences in the exposure pre-and post-surgery.In addition,the CYP2C19 genotype as well as liver function significantly affected the clearance of omeprazole.Conclusion(1)The apparent clearance of omeprazole was lower in obese patients compared to normal-weight adults.Therefore,obese patients may require a lower daily dose of omeprazole for long-term use,especially for CYP2C19 poor metabolizers.In addition,obese patients with mild liver dysfunction may require a lower initial dose and regular monitoring of liver function.(2)On the 7th day after sleeve gastrectomy,the absorption rate of omeprazole increased compared to the preoperative values,but the change in exposure was not observed.Hence,20 mg once daily of omeprazole for patients undergoing sleeve gastrectomy may be sufficient to relieve shortterm symptoms of gastrointestinal discomfort and to prevent gastric ulcers after surgery.