Bariatric Surgery, Drug Absorption, Obesity & Overweight, Pharmacokinetics After Oral Intake
Conditions
Keywords
Roux-en-Y gastric bypass, sleeve gastrectomy, rosuvastatin, losartan, E-3174, gut microbiota, metabolomics, systemic exposure
Brief summary
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.
Detailed description
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.
Interventions
DRUGRosuvastatin
Rosuvastatin 10 mg tablet, single oral dose at each of two pharmacokinetic visits. Other name: rosuvastatin calcium.
Losartan 25 mg tablet, single oral dose at each of two pharmacokinetic visits. Other name: losartan potassium.
Sponsors
Hospital das Clínicas de Ribeirão Preto
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Participants enter the RYGB or sleeve gastrectomy group according to the operation selected for clinical care. Within each group, every participant undergoes identical paired pharmacokinetic test-dose visits before and after surgery.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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.
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in rosuvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 apparent oral clearance (CL/F) of rosuvastatin, losartan, and E-3174; same two study visits. |
| 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 estimated elimination half-life of rosuvastatin, losartan, and E-3174; same two study visits. |
| 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). | Change in plasma concentrations of rosuvastatin, losartan, and E-3174 at 1.5 and 4 hours after the single oral dose; each pharmacokinetic visit. |
| 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). | 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. |
| 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), change in gut microbial alpha diversity (Shannon and Simpson indices) in paired stool samples; preoperative and approximately 12 weeks postoperative. |
| 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). | In the RYGB group only (30 participants), differential abundance of gut microbial taxa in paired stool samples; preoperative and approximately 12 weeks postoperative. |
| 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 | Change in apparent volume of distribution of rosuvastatin, losartan, and E-3174; same two study visits. |
| 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 beta diversity (Bray-Curtis, Jensen-Shannon, and Jaccard distances) in paired stool samples; preoperative and approximately 12 weeks postoperative. |
| 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). | In the RYGB group only (30 participants), change in untargeted fecal metabolomic features in paired stool samples; preoperative and approximately 12 weeks postoperative. |
| 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 percent change in rosuvastatin AUC0-inf and change in gut microbiota alpha diversity. Plasma concentrations are measured by HPLC-MS/MS at predose, 1.5, and 4 hours; AUC0-inf (ng\*h/mL) is estimated by maximum a posteriori Bayesian estimation. Percent AUC change = 100 x \[(postoperative - preoperative)/preoperative\]. In paired fecal samples from the Roux-en-Y gastric bypass group, V3-V4 16S rRNA sequencing with Illumina MiSeq is used to calculate the unitless Shannon Diversity Index; change = postoperative - preoperative. Pearson's r is unitless and ranges from -1 to +1. Positive values indicate changes in the same direction, negative values indicate changes in opposite directions, and absolute values closer to 1 indicate stronger correlation. |
| 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). | Pearson correlation between percent change in losartan AUC0-inf and change in gut microbiota alpha diversity. Plasma concentrations are measured by HPLC-MS/MS at predose, 1.5, and 4 hours; AUC0-inf (ng\*h/mL) is estimated by maximum a posteriori Bayesian estimation. Percent AUC change = 100 x \[(postoperative - preoperative)/preoperative\]. In paired fecal samples from the Roux-en-Y gastric bypass group, V3-V4 16S rRNA sequencing with Illumina MiSeq is used to calculate the unitless Shannon Diversity Index; change = postoperative - preoperative. Pearson's r is unitless and ranges from -1 to +1. Positive values indicate changes in the same direction, negative values indicate changes in opposite directions, and absolute values closer to 1 indicate stronger correlation. Time Frame |
Countries
Brazil
Contacts
CONTACTWilson Salgado Jr, MD, PhD
CONTACTJoao A Ferreira-Filho, MD
PRINCIPAL_INVESTIGATORWilson Salgado Jr, MD PhD
Medical School of Ribeirao Preto, University of Sao Paulo
Outcome results
None listed