Pharmacokinetics of Simvastatin Post Laparoscopic Sleeve Gastrectomy (LSG)

The Need of Dosing Adjustment for Simvastatin in Obese Patients Post Bariatric Surgery- Laparoscopic Sleeve Gastrectomy (LSG)

This study aims to investigate the change in systemic exposure of simvastatin post LSG.

Study Overview

• Status: Recruiting
• Conditions: Obesity; Hyperlipidemias
• Intervention / Treatment: Drug: Simvastatin

Detailed Description

Morbid obesity (Body mass index > 40 kg/m2 or 35-39 kg/m2 with comorbidity; 37.5 kg/m2 for Asians) is a growing global health issue. Bariatric surgery is the only intervention that has demonstrated sustainable reduction in weight and comorbidities.1,2 Among the various bariatric procedures, laparoscopic sleeve gastrectomy (LSG) has rapidly gained popularity worldwide.3,4 Physiological alterations following LSG include reduction in gastrointestinal surface and reduced retention of food. Bioavailability of drugs may be affected but published literature in this area is sparse and studies are usually small and uncontrolled.5-7 Moreover, some reports concerning gastric banding and jejunoileal bypass are no longer practiced because of the associated risk. In general, bioavailability of orally administered drug changes with a reduction in gastrointestinal area. While Kroll et al showed slight increase in area under curve of rivaroxaban post bariatric surgery8, Skottheim et al demonstrated significant but variable change in systemic exposure of atorvastatin after gastric bypass (from threefold decrease to twofold increase) that diminished but was sustained with time (21-45 months post gastric bypass)9-10.

No study has investigated the change in pharmacokinetics of simvastatin post LSG.

Simvastatin is a widely-used lipid-lowering agent with a low bioavailability of 5% due to the extensive first pass metabolism.11 As simvastatin undergoes hydrolysis in the stomach to the active form12, it is postulated that bioavailability of simvastatin will decrease after LSG.13-15 A decrease in bioavailability may be associated with reduced efficacy. Authors of review articles suggested choosing an alternative agent to simvastatin post bariatric surgery. However, such recommendation is largely based on theoretical concern rather than solid evidence.14,15 A previous study attempted to model the pharmacokinetics of simvastatin post Roux-en-Y and biliopancreatic diversion with duodenal switch.13 The data is not applicable to LSG and the model did not take into account of the pH-dependent hydrolysis. This will be the first study aiming to investigate the change in systemic exposure of simvastatin post LSG.

• Study Type: Interventional
• Enrollment (Anticipated): 10
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Asim Shabbir, MBBS; Phone Number: +65 9820 0814; Email: cfsasim@nuhs.edu.sg
• Study Contact Backup: Name: Elaine Lo, PharmD; Phone Number: +65 9877 2682; Email: elaine_lo@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • Recruiting
    • National University Hospital
    • Contact: Elaine Lo, PharmD; Phone Number: +65 9877 2682; Email: elaine_lo@nuhs.edu.sg
    • Contact: Asim Shabbir, MBBS; Phone Number: +65 9820 0814; Email: cfsasim@nus.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Planned for laparoscopic sleeve gastrectomy at National University Hospital
• Taking statin
• Aged 21 or above

Exclusion Criteria:

• Patient on concomitant treatment with medications/ food/ herbal supplements that may affect the pharmacokinetics of simvastatin: boceprevir, conivaptan, cyclosporine, efavirenz, mitotane, tocilizumab, rifamycin, amiodarone, amlodipine, aprepitant, azithromycin, colchicine, fenofibrate, imatinib, raltegravir, ranolazine, teriflunomide, ticagrelor, fusidic acid, protease inhibitors, telaprevir, telithromycin, gemfibrozil, erythromycin, clarithromycin, carbamazepine, rifampicin, ketoconazole, fluconazole, itraconazole, voriconanzole, diltiazem, verapamil, dexamethasone, prednisolone, phenytoin, ritonavir, indinavir, nelfinavir, bosentan, telithromycin, nefazodone, St John's wort, orlistat, sibutramine and other strong CYP 3A4 inhibitors/ inducers
• Pregnant ladies

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: intervention arm; simvastatin 20mg once	Drug: Simvastatin; The subject will take simvastatin 20mg at 0 h (after stopping simvastatin for 5 days). 5 mL of blood will be sampled at 0 h, 1 h, 2 h, 3 h, 5 h, 7 h.; There will be 2 blood sampling sessions: 1 before and the other 3 months after surgery.; Other Names: Study arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Curve (AUC) of simvastatin	Ratio of AUC of simvastatin for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery
Maximum serum concentration (Cmax) of simvastatin	Ratio of Cmax of simvastatin for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery
Time at which maximum serum concentration (Tmax) of simvastatin	Ratio of Tmax of simvastatin for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery
Area Under Curve (AUC) of simvastatin acid	Ratio of AUC of simvastatin acid for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery
Maximum serum concentration (Cmax) of simvastatin acid	Ratio of Cmax of simvastatin acid for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery
Time at which maximum serum concentration (Tmax) of simvastatin acid	Ratio of Tmax of simvastatin acid for each subject before and 3 months after surgery will be calculated, the mean ratio will be reported	baseline (before surgery). 3 months after surgery

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Investigators: Principal Investigator: Asim Shabbir, MBBS, National University Hospital, Singapore

Publications and helpful links

General Publications

• Skottheim IB, Stormark K, Christensen H, Jakobsen GS, Hjelmesaeth J, Jenssen T, Reubsaet JL, Sandbu R, Asberg A. Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients. Clin Pharmacol Ther. 2009 Sep;86(3):311-8. doi: 10.1038/clpt.2009.82. Epub 2009 Jun 3.
• Jakobsen GS, Skottheim IB, Sandbu R, Christensen H, Roislien J, Asberg A, Hjelmesaeth J. Long-term effects of gastric bypass and duodenal switch on systemic exposure of atorvastatin. Surg Endosc. 2013 Jun;27(6):2094-101. doi: 10.1007/s00464-012-2716-3. Epub 2012 Dec 18.

Helpful Links

• Pharmacokinetics and pharmacodynamics of single doses of rivaroxaban in obese patients prior to and after bariatric surgery

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 13, 2018
• Primary Completion (ANTICIPATED): June 30, 2025
• Study Completion (ANTICIPATED): June 30, 2025

Study Registration Dates

• First Submitted: May 22, 2018
• First Submitted That Met QC Criteria: June 17, 2018
• First Posted (ACTUAL): June 28, 2018

Study Record Updates

• Last Update Posted (ACTUAL): April 8, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: bariatric surgery; pharmacokinetics; simvastatin; laparoscopic sleeve gastrectomy
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hyperlipidemias; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: LSGSIMVASTATIN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No plan to share IPD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes