Pharmacokinetics of Simvastatin Post Laparoscopic Sleeve Gastrectomy (LSG)

Obesity Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03571802
• Other study ID #: LSGSIMVASTATIN
• Status: Recruiting
• Phase: Phase 4
• Start date: June 13, 2018
• Est. completion date: June 30, 2025

Study information

• Verified date: April 2022
• Source: National University Hospital, Singapore
• Contact: Asim Shabbir, MBBS
• Phone: +65 9820 0814
• Email: cfsasim[@]nuhs.edu.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: June 30, 2025
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hyperlipidemias
• Obesity

Intervention

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.

Locations

Country	Name	City	State
Singapore	National University Hospital	Singapore

Sponsors (1)

Lead Sponsor	Collaborator
National University Hospital, Singapore

Country where clinical trial is conducted

Singapore, 

References & Publications (2)

Jakobsen GS, Skottheim IB, Sandbu R, Christensen H, Røislien J, Asberg A, Hjelmesæth 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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

External Links

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