Comparative Evaluation of Rosuvastatin and Losartan Pharmacokinetics and the Associations Between Gut Microbiota Alterations and Changes in Systemic Drug Exposure in Patients Undergoing Roux-en-Y Gastric Bypass or Sleeve Gastrectomy
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in rosuvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity)
研究概览
简要总结
This prospective, open-label, non-randomized pharmacokinetic study will evaluate how Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy affect systemic exposure to single oral test doses of rosuvastatin and losartan. Sixty adults scheduled for bariatric surgery will enter one of two parallel groups according to the clinically selected operation (30 RYGB and 30 sleeve gastrectomy). Each participant will receive rosuvastatin 10 mg and losartan 25 mg once within 30 days before surgery and again approximately 12 weeks after surgery. Plasma samples collected before dosing and at 1.5 and 4 hours after dosing will be used with maximum a posteriori Bayesian estimation to estimate individual pharmacokinetic parameters. In the 30-participant RYGB group only, paired stool samples will be used to explore gut microbiota and untargeted fecal metabolomic changes. The primary objective is to compare within-participant changes and between-procedure differences in drug exposure after bariatric surgery.
详细描述
Anatomical and physiological changes after bariatric surgery may alter oral drug absorption, first-pass metabolism, transporter activity, and systemic exposure. RYGB bypasses the duodenum and proximal jejunum, whereas sleeve gastrectomy preserves intestinal continuity but reduces gastric volume and may accelerate gastric emptying. Rosuvastatin is strongly influenced by transporters such as OATP1B1 and BCRP; losartan is affected by absorption and CYP2C9-mediated formation of its active metabolite E-3174. Direct comparative evidence between these procedures is limited.
Eligible adults will be enrolled before clinically indicated surgery. Surgical procedure selection is not assigned by the study. At each pharmacokinetic visit, after at least 8 hours of fasting, participants will receive single oral doses of rosuvastatin 10 mg and losartan 25 mg with 200 mL water. Venous plasma samples will be obtained at 0, 1.5, and 4 hours. Concentrations of rosuvastatin, losartan, and E-3174 will be quantified using validated HPLC-MS/MS. Individual AUC0-infinity, apparent clearance, half-life, and apparent volume of distribution will be estimated using MAP Bayesian methods informed by published population pharmacokinetic models. Clinical and laboratory covariates, including weight, BMI, lipid profile, blood pressure, comorbidities, and concomitant medications, will be recorded. In the 30-participant RYGB group only, paired stool samples will be analyzed by 16S rRNA sequencing and untargeted metabolomics. Safety will be monitored during and after each research dosing visit.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults aged 18 to 65 years;
- •Formal clinical indication for RYGB or sleeve gastrectomy after multidisciplinary assessment;
- •Bariatric surgery scheduled and no previous bariatric procedure;
- •Able to understand the study and provide written informed consent.
排除标准
- •Moderate or severe hepatic impairment, liver enzymes greater than 3 times the upper limit of normal, or Child-Pugh class B or C.
- •Estimated glomerular filtration rate below 30 mL/min/1.73 m².
- •Concomitant use of drugs that substantially affect rosuvastatin pharmacokinetics and cannot be temporarily discontinued, including cyclosporine, gemfibrozil, or potent OATP1B1/BCRP or CYP2C9 inhibitors.
- •Systemic antibiotic use within 3 months or probiotic, prebiotic, or synbiotic use within 4 weeks before sampling.
- •Continuous current rosuvastatin or other statin therapy unless medically discontinued with an adequate washout period under physician supervision.
- •Clinically relevant baseline hypotension, significant hyperkalemia, renal impairment, or another condition that makes a losartan test dose unsafe.
- •Severe postoperative complication preventing oral dosing, including active gastrointestinal leak, intractable vomiting, or severe anastomotic stenosis.
- •Pregnancy. Participants of childbearing potential undergo routine preoperative beta-hCG testing.
研究组 & 干预措施
Sleeve Gastrectomy Group
Participants scheduled for clinically indicated laparoscopic sleeve gastrectomy receive the same single oral research doses and pharmacokinetic plasma sampling schedule before and approximately 12 weeks after surgery. Stool collection and microbiome/metabolomics analyses are not performed in this group.
干预措施: Rosuvastatin (Drug)
Sleeve Gastrectomy Group
Participants scheduled for clinically indicated laparoscopic sleeve gastrectomy receive the same single oral research doses and pharmacokinetic plasma sampling schedule before and approximately 12 weeks after surgery. Stool collection and microbiome/metabolomics analyses are not performed in this group.
干预措施: Losartan (Control) (Drug)
Roux-en-Y Gastric Bypass Group
Participants scheduled for clinically indicated laparoscopic RYGB receive a single oral research dose of rosuvastatin 10 mg plus losartan 25 mg within 30 days before surgery and again approximately 12 weeks after surgery. Plasma is collected at 0, 1.5, and 4 hours at each visit. Paired stool samples are collected before and after surgery for microbiome and untargeted metabolomics analyses.
干预措施: Rosuvastatin (Drug)
Roux-en-Y Gastric Bypass Group
Participants scheduled for clinically indicated laparoscopic RYGB receive a single oral research dose of rosuvastatin 10 mg plus losartan 25 mg within 30 days before surgery and again approximately 12 weeks after surgery. Plasma is collected at 0, 1.5, and 4 hours at each visit. Paired stool samples are collected before and after surgery for microbiome and untargeted metabolomics analyses.
干预措施: Losartan (Control) (Drug)
结局指标
主要结局
Change in rosuvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity)
时间窗: Within 30 days before surgery and approximately 12 weeks after surgery (postoperative visit may be delayed up to 6 months for clinical safety).
Individual rosuvastatin AUC0-infinity will be estimated from plasma concentrations at 0, 1.5, and 4 hours using maximum a posteriori Bayesian estimation based on a published population pharmacokinetic model. Within-participant postoperative/preoperative geometric mean ratios and between-procedure differences will be estimated.
Change in losartan area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity)
时间窗: Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).
Individual losartan AUC0-infinity will be estimated using the same sparse-sampling MAP Bayesian strategy and a published parent-metabolite population model.
次要结局
- Change in apparent oral clearance (CL/F) of rosuvastatin, losartan, and E-3174; same two study visits.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- Change in estimated elimination half-life of rosuvastatin, losartan, and E-3174; same two study visits.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- Change in plasma concentrations of rosuvastatin, losartan, and E-3174 at 1.5 and 4 hours after the single oral dose; each pharmacokinetic visit.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- Incidence of adverse events following research test dosing, assessed from dose administration through completion of the 4-hour observation period at each visit and by clinically indicated follow-up.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- In the RYGB group only (30 participants), change in gut microbial in paired stool samples(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- In the RYGB group only (30 participants), differential abundance of gut microbial taxa in paired stool samples(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- Change in apparent volume of distribution of rosuvastatin, losartan, and E-3174; same two study visits.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months)
- In the RYGB group only (30 participants), change in beta diversity (Bray-Curtis, Jensen-Shannon, and Jaccard distances) in paired stool samples; preoperative and approximately 12 weeks postoperative.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- In the RYGB group only (30 participants), change in untargeted fecal metabolomic features in paired stool samples; preoperative and approximately 12 weeks postoperative.(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)
- Pearson Correlation Between Percent Change in Rosuvastatin Systemic Exposure and Change in Gut Microbiota Shannon Diversity Index(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety))
- Pearson Correlation Between Change in Losartan AUC0-inf and Change in Gut Microbiota Shannon Diversity Index(Within 30 days before surgery and approximately 12 weeks after surgery (up to 6 months if delayed for clinical safety).)