The Need of Dosing Adjustment for Simvastatin in Obese Patients Post Bariatric Surgery- Laparoscopic Sleeve Gastrectomy (LSG)
Phase: PHASE4
Conditions: Obesity, Hyperlipidemias
Sponsor: National University Hospital, Singapore

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Study Protocol 
 
Title: The Need of Dosing Adjustment for Simvastatin in Obese Patients post Bariatric Surgery- 
Laparoscopic sleeve gastrectomy (LSG) 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Abstract  
 
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. 
 
Aims & Objectives  
 
The aim of the study is to investigate the effect of laparoscopic sleeve gastrectomy on the 
pharmacokinetics of simvastatin. 
 
Study design 
 
Study design:  prospective, open, non-randomized, controlled, single-centre study  
The study will be conducted with the approval from the Institutional Ethics and Research Board. 
Participants: 10 patients undergoing sleeve gastrectomy 
 

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Study Procedure 
- 
Patient recruitment 
o Subject selection:  
 
Inclusion criteria:  
 
Planned for laparoscopic sleeve gastrectomy at National University 
Hospital 
 
Taking simvastatin 
 
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 inihibitors/ inducers 
 
Pregnant ladies 
o All patients referred to the National University Hospital for laparoscopic sleeve 
gastrectomy will be screened for inclusion into the study. Potential subjects will be 
screened and assessed at the Bariatric Surgery Clinic. Written consent will be taken at the 
Clinic. ( See Patient consent form) The potential subject’s permission to be referred into 
a study will be obtained by the attending healthcare professionals prior to direct contact 
by any member of the research team, and the subject’s agreement will be documented. 
The study aims to recruit 10 patients. 
o Patients will be asked to stop taking simvastatin 5 days before the day of the study. 
Fasting is not required. Patients will also be informed that they will obtain SGD $100 after 
completing the study as a token of appreciation and to compensate their time and 
inconvenience (if the study subject fails to complete the study, compensation will be pro-
rated and paid out as $50 per each blood sampling session). 
- 
Training  
o Study members, namely Elaine Lo, Subashini Gunasegaran, Yeoh Siang Fei, will be trained 
for the following: 1) Explaining procedure of the study to recruited study subjects after 
informed consent is taken; 2) Delivering blood sample from the bariatric clinic to the lab 
for storage and 3) Procedures for compensating the patient after the study 
o Nurses of the bariatric clinic will be trained to administer the study according to the study 
protocol: 1) Making sure study subject is suitable for blood sampling e.g. has stopped 
simvastatin for 5 days, vitals stable, IV plug properly set by physician; 2) Monitoring self-
administration of simvastatin by the patient; 3) Drawing blood according to the pre-set 
time points; 4) Monitoring patient for vitals and comfort after blood draw; 5) 
Documentation of details of blood sampling on the “Record for Blood Sampling” 
o The training details (i.e. date, name of trainee and trainer, contents of training) will be 
recorded. Training records will be kept for 3 years after completion of the study. 
- 
Pre-bariatric surgery 

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o Recruited subjects will come to the clinic at 8:30am on the day of study. Blood taking will 
start at 9:30am. Fasting is not required.  
o Nurses at the Bariatric Surgery Clinic will set an IV plug for blood sampling. They will also 
confirm with the subjects that simvastatin has been stopped for 5 days. Nurses will also 
check that patient has not been taking the interacting drugs in the past 5 days. The subject 
will take simvastatin 20mg at 9:30am (0 h). 5 mL of blood will be sampled at 0 h, 1 h, 2 h, 
3 h, 5 h, 7 h. Blood sample will be taken in EDTA tubes and kept in ice. (See Record of 
blood sampling). Study subjects wll be staying at the Bariatric Surgery Clinic and 
monitored by nurses who are trained for care and monitoring of patients with IV 
cannulation. 
o All the blood samples will be transferred to the lab in ice after the last blood sample is 
drawn at 7 h. Blood samples will be spun down and frozen. 
- 
Surgical procedure 
o Laparoscopic sleeve gastrectomy (LSG) is performed for most patients requiring bariatric 
surgery at the National University Hospital. This is a restrictive procedure where the 
stomach is tubularized and the excess part is removed. About 75% of the stomach will be 
removed in this way. 
- 
Post-bariatric surgery 
o Patients will be invited to return to the clinic for another blood sampling session after 3 
months. If the patient takes proton pump inhibitor prior to the study, the same dose 
should be maintained at 3 months when the patient returns for the study.  
o The blood sampling procedure for pre-bariatric surgery will be repeated. 
o $100 will be given to patient upon completion of the second blood sampling session. 
 
Blood sample analysis 
- 
Liquid chromatography–mass spectrometry (LC-MS) will be run when samples for all the patients 
(10) are collected.  
 
Statistical Analysis 
- 
Pharmacokinetic parameters (Area under curve, half life, Tmax and Cmax) of simvastatin and 
simvastatin acid before and after bariatric surgery will be calculated for each subject using 
pharmacokinetics software. (See Pharmacokinetics Evaluation Form) Each patient will serve as 
their own control and pharmacokinetic parameters before and after LSG will be compared with 
appropriate statistical tests (student t-test if parametric, mann-whitney u test if non-parametric).  
 
 
 

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