Clinical trial NCT03571802: Pharmacokinetics of Simvastatin Post Laparoscopic Sleeve Gastrectomy (LSG)
Official title: The Need of Dosing Adjustment for Simvastatin in Obese Patients Post Bariatric Surgery- Laparoscopic Sleeve Gastrectomy (LSG)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Obesity
Hyperlipidemias
Keywords: pharmacokinetics
simvastatin
bariatric surgery
laparoscopic sleeve gastrectomy
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
First posted: 2018-06-28
Enrollment: 10
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Pharmacokinetic parameters of simvastatin before and after laparoscopic sleeve gastrectomy will be compared in 10 patients. Each patient will serve as their own control for comparison.
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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

Primary outcomes:
measure: Area Under Curve (AUC) of simvastatin
timeFrame: baseline (before surgery). 3 months after surgery
measure: Maximum serum concentration (Cmax) of simvastatin
timeFrame: baseline (before surgery). 3 months after surgery
measure: Time at which maximum serum concentration (Tmax) of simvastatin
timeFrame: baseline (before surgery). 3 months after surgery
measure: Area Under Curve (AUC) of simvastatin acid
timeFrame: baseline (before surgery). 3 months after surgery
measure: Maximum serum concentration (Cmax) of simvastatin acid
timeFrame: baseline (before surgery). 3 months after surgery
measure: Time at which maximum serum concentration (Tmax) of simvastatin acid
timeFrame: baseline (before surgery). 3 months after surgery
Secondary outcomes:
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Asim Shabbir, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.