Bariatric Surgery and Pharmacokinetics Lisdexamphetamine: BAR-MEDS Lisdexamphetamine
Conditions: Obesity, Morbid
Sponsor: Norwegian University of Science and Technology

Protocol 
The BAR-MEDS study: Changes in Drug Pharmacokinetics After 
Bariatric Surgery – a Series of Prospective studies 
 
COMMENT/COVER PAGE 
The study includes pharmacokinetic measurements of a range of different drugs. For technical 
reasons, and as adviced from the ClinTrials-contact person at the university, the study was 
registered on ClinicalTrials.gov as separate, drug-specific entries. Consequently, this document 
pertains to the entries: 
- 
NCT03440190 (methylphenidate) 
- 
NCT03460379 (escitalopram) 
- 
NCT03460353 (dexamphetamine) 
- 
NCT03460210 (atomoxetine) 
- 
NCT03497169 (lisdexamphetamine) 
- 
NCT03532477 (venlafaxine) 
- 
NCT02904291 (amlodipine) 
- 
NCT03538457 (paracetamol) 
- 
NCT03535376 (valsartan) 
- 
NCT03519893 (losartan) 
- 
NCT03519906 (metoprolol) 
- 
NCT03497143 (lamotrigine) 
- 
NCT03497156 (lercanidipine) 
- 
NCT03476525 (fluoxetine) 
- 
NCT03476538 (gabapentin) 
- 
NCT03476551 (hydrochlorothiazide) 
- 
NCT03476603 (irbesartan) 
- 
NCT03476577 (ibuprofen) 
- 
NCT03449472 (quetiapine) 
- 
NCT03460314 (buprenorphine) 
- 
NCT03460327 (candesartan) 
- 
NCT03460366 (enalapril) 
- 
NCT03449485 (chlorprothixene) 
- 
NCT03448783 (apixaban) 
- 
NCT03440177 (ramipril) 
Since ClinicalTrials.gov in retrospect requires documents in English, the protocol was translated 
afterward using ChatGPT. 
Version 1, June 13, 2016 – translated Oct 30, 2024 
Magnus Strømmen, Arne Helland, Bård Kulseng, Olav Spigset 
IRB-reference: 2016/1145 

Background 
Each year, more than half a million obesity surgeries (bariatric procedures) are performed 
globally, with approximately three thousand of these at public hospitals in Norway. In 
Norway, surgeries are mainly divided into two procedures: gastric bypass and sleeve 
gastrectomy. Both are conducted to limit nutrient absorption. 
However, the gastrointestinal tract also plays a crucial role in the absorption of orally 
administered drugs. 95% of patients referred for bariatric surgery are multimorbid, and a 
comparable data study indicated that patients referred for bariatric surgery use an average of 
4.4 different medications. Medications for diabetes, depression, and hypertension are most 
common. These conditions may remit after surgery, but most patients still require some level 
of medication afterward. 
The Bariatric Procedures 
The surgeries are generally performed laparoscopically by experienced surgeons. 
In gastric bypass, a portion of the stomach (cardia) is separated and transformed into a small 
pouch, approximately the size of an egg, and connected to part of the small intestine. The 
remaining stomach, duodenum, and about a meter of the small intestine are left behind, 
rendering them inactive in terms of absorption. Instead, food bypasses the stomach directly 
into a more distal section of the small intestine, only meeting gastric juices, bile, and 
pancreatic enzymes approximately one meter downstream. This setup creates both a 
restrictive and malabsorptive effect on the intestine. 
Sleeve gastrectomy is a simpler procedure with no anastomosis (and thus reduced leakage 
risk). Around 80% of the stomach’s outer curvature is removed, creating a tubular stomach 
(providing some restriction in intake) while preserving the pylorus (sphincter) and part of the 
antrum. Despite maintaining more normal anatomy, the physiological effects are likely greater 
than previously assumed, possibly due to significantly increased gastric emptying speed in the 
new stomach, even with the preserved pyloric sphincter. 
Surgery and Bioavailability of Enteral Drugs 
The gastrointestinal system significantly affects the bioavailability of oral drugs. Factors such 
as gastric pH and emptying rate, intestinal transit time, and first-pass metabolism due to 
mucosal enzymes can impact a drug's bioavailability. It is reasonable to expect that both 
gastric bypass and sleeve gastrectomy surgeries may influence several of these factors. 
Changed bioavailability and pharmacokinetics of medications can have serious 
implications for patients, especially when a drug is essential or has a narrow therapeutic 
window. This issue has periodically been raised by bariatric surgeons, with the uncertainty 
around potential reductions in drug bioavailability sometimes used as an argument against 
surgical intervention for certain patients. In cases where surgery is reluctantly approved, 
sleeve gastrectomy has been preferred due to the assumption of lesser physiological impact 
(i.e., more normal anatomy). 
However, bariatric surgery can also have the opposite effect on bioavailability. For drugs 
metabolized presystemically in the mucosa (stomach and/or intestines), the surgeries may 

increase bioavailability. Examples include increased bioavailability of methadone after sleeve 
gastrectomy and ethanol following both sleeve gastrectomy and gastric bypass. 
Only a limited number of drugs have been studied concerning the pharmacokinetic effects of 
bariatric surgeries. Most studies are small and have methodological weaknesses. The high 
number of bariatric surgeries, the fact that patients are typically multimorbid and use multiple 
medications, and our incomplete understanding of the surgeries' physiological effects 
underscore the need for more data. This document describes a project designed to investigate 
the pharmacokinetics of various drugs used by this patient population. 
Study Objective 
The purpose of the study is to map changes in the bioavailability of medications after 
undergoing sleeve gastrectomy and gastric bypass (among obesity patients). This includes 
examining bioavailability and pharmacokinetics in both the short and long term. 
The primary endpoint will be bioavailability (AUC – ‘area under the curve’), as a measure of 
the body’s total exposure to the drug. Qualitative data such as Cmax (maximum drug 
concentration) and Tmax (time to reach Cmax) will also be included. 
Study Design 
The study will consist of a series of smaller studies, where each drug and each procedure 
define the individual study. Randomized crossover studies are not possible since the surgeries 
are irreversible; however, we will use the patients as their own controls, making the results 
more reliable with fewer participants needed. 
The drugs relevant for study are those that the Department of Clinical Pharmacology has 
analytical methods for (see appendix). These include most psychopharmaceuticals, 
antiepileptics, analgesics, blood pressure medications, and a variety of other drugs. 
Data Collection 
Descriptive Data 
 
Gender, age, medical history, and medication use – collected from patient records. 
Blood Samples 
 
Baseline blood tests for hemoglobin (Hb), aspartate aminotransferase (ASAT), alanine 
aminotransferase (ALAT), gamma-glutamyl transferase (GT), alkaline phosphatase (ALP), 
albumin, total bilirubin, international normalized ratio (INR), creatinine, C-reactive protein 
(CRP), and orosomucoid. 
 
Serum concentration of the drug as a basis for pharmacokinetic analysis. 
 
Blood sample for pharmacogenetic analysis of CYP enzymes and possibly other drug-
metabolizing enzymes. 
 
Blood for biobank storage. 

Additional Measurements 
 
Body composition analysis (bioelectrical impedance analysis) for distribution volume 
calculation. 
Procedures 
Participants arrive in the morning, either at the Research Unit or at the Center for Obesity 
Research at St. Olavs Hospital. Medication will be administered under observation by study 
personnel. 
Participants must arrive fasting, meaning: 
 
Clear fluids can be consumed up to 2 hours before arrival. 
 
Coffee, grapefruit juice, and tobacco should be avoided from midnight the night before. 
 
One hour after medication administration, the participant is given a standardized meal, while 
subsequent meals are taken according to the participant's preference. 
Sample collection procedures will depend on the drug’s half-life. Drugs administered once, 
twice, or three times daily will each follow a specific sampling schedule, ensuring that the 
total blood volume drawn remains within safe limits. For example, a full 24-hour series for up 
to two drugs will involve a total of 89 ml, including discarded blood. For patients with three 
or more drugs, the blood volume will be doubled (178 ml). No more than this amount will be 
collected. By comparison, blood donors typically give 500 ml in one donation. 
Administration 
Frequency 
Biobank
Initial 
Sample
0.5 
hr
1 
hr
1.5 
hr
2 
hr
2.5 
hr
3 
hr
3.5 
hr
4 
hr
6 
hr
8 
hr
12 
hr
24 
hr
Total Blood 
Volume (incl. 
discarded 
samples) 
Once a day 
X 
X 
X 
X X 
X X 
X X 
X X X X 89 
ml  
Twice a day 
X 
X 
X 
X X 
X X 
X X 
X X  
 
82 
ml  
Three times a day X 
X 
X 
X X 
X X 
X X 
X  
 
 
82 
ml  
Sample Handling Samples are collected in 5 ml serum tubes without gel (red with black ring) 
at each sampling time point. If a venflon is used, 2-3 ml of blood is discarded before 
collection. Tubes are allowed to coagulate for 30 minutes before centrifugation at room 
temperature for 10 minutes at 2200xG. Serum is pipetted into Nunclon tubes (2 ml) and 
labeled with the relative sampling time. Samples are stored in a refrigerator until they are 
collectively sent to the Department of Clinical Pharmacology. If samples are collected on a 
weekend, they are stored in a refrigerator until the next weekday. 
Blood samples for pharmacogenetic analysis are taken in EDTA tubes and sent directly to the 
relevant department, typically the Department of Medical Genetics at St. Olavs Hospital. 

Additionally, two EDTA tubes and one serum tube are collected per test day for biobanking. 
The serum is divided into two Nunclon tubes, frozen, and registered in the BAR-MEDS 
biobank. Biobank1 is the data processor for the BAR-MEDS biobank, utilizing Biobank1’s 
infrastructure (software, barcode labels) to achieve the same quality control as other Biobank1 
projects. Unless designated otherwise by the clinic manager, the project leader will be 
responsible for the BAR-MEDS biobank. 
Testing Schedule 
Testing of serum drug concentration will occur at the following time points: 
 
Preoperative 
 
One week after surgery 
 
One month after surgery 
 
Six months after surgery 
 
One year after surgery 
The first test can be conducted at any time prior to surgery, except immediately preoperatively 
if the patient is on a low-calorie diet. In addition to a baseline test, four postoperative test 
points are chosen. The rationale for several postoperative tests over time has multiple aspects. 
Shortly after surgery, the mucosa might be edematous, potentially affecting presystemic 
metabolism. Additionally, these patients enter a catabolic state and experience significant 
weight loss over the first year, which may indirectly affect drugs for which body mass 
determines the volume of distribution. Repeated postoperative tests will thus help indicate the 
physiological processes taking place in the body, such as whether bioavailability changes 
occur more quickly than can be attributed to distribution volume changes alone. Another 
reason for multiple tests is that patients will typically need adequate medication throughout 
this period. Finally, if there is a clear trend in pharmacokinetic changes across these tests, it 
may suggest that we have not yet reached a final and stable post-surgical effect by the one-
year test. 
Test Dose 
The patient will take the prescribed drug as directed by their own physician. Participation in 
the study thus involves no changes to medication or prescription of new drugs. 
Participant Selection 
Inclusion Criteria 
Group 1: 
Patients with morbid obesity scheduled for gastric bypass at St. Olavs Hospital or Namsos 
Hospital. 
Group 2: 
Patients with morbid obesity scheduled for sleeve gastrectomy at St. Olavs Hospital or 
Namsos Hospital. 
Exclusion Criteria 
 
Previous intestinal resection 

 
Lack of capacity to give informed consent 
Sample Size 
Bioequivalence studies follow a standard study design recommending at least 12 participants 
per group. Since the study comprises a series of individual drug studies (one study per drug 
per surgical technique), the hypothetical maximum number of participants could be: 12 
participants x 2 surgical techniques x 109 drugs = 2,616 participants. 
The actual number will be significantly lower, primarily because many patients are 
multimorbid and use several drugs simultaneously. In such cases, multiple drugs can be 
analyzed within the blood volume limits. Given that participants in the study use an average 
of 2.5 drugs within the study’s analytical range (the average number of medications is 4.4), 
approximately 1,000 participants are expected. Each year, up to 100 patients in Trondheim 
and 200 in Namsos undergo the surgical techniques under study, with additional patients at 
the private Volvat Stokkan clinic. Considering the volume of bariatric surgeries is increasing, 
and that the study structure allows for a separate sub-study for each drug, this study is 
feasible. 
Recruitment Procedure 
The obesity clinic physicians lack the capacity to systematically review patients' medication 
lists for study inclusion. Therefore, a researcher affiliated with the Center for Obesity 
Research at St. Olavs Hospital will review referrals for patients undergoing bariatric surgery 
evaluation. The Center for Obesity Research, an entity within St. Olavs, is physically and 
organizationally integrated with the Obesity Clinic. 
The researcher will note patients taking relevant medications, and the physician involved in 
the assessment will provide initial information about the study. Patients who express 
disinterest in participation or in learning more about the study will not be approached further. 
Other patients will be contacted by the researcher with more information about the study for 
potential inclusion. 
For patients at Namsos Hospital and Volvat Stokkan, the same will occur in collaboration 
with a nurse or surgeon associated with the surgical operations, either through direct 
coordination or review of referrals. Referrals at St. Olavs Hospital and Namsos Hospital will 
be accessed via Doculive. 
Research Environment 
Collaborators and Research Team 
Center for Obesity Research, St. Olavs Hospital. The study is led by the center, which is 
mandated to develop and evaluate treatment methods for obesity, focusing on patient-centered 
clinical research. 
 
Research Nurse Magnus Strømmen (Project Leader), St. Olavs Hospital 
 
Professor Bård Kulseng, St. Olavs Hospital 
 
Chief Physician Ronald Mårvik, St. Olavs Hospital 

Department of Clinical Pharmacology, St. Olavs Hospital. The department is one of the 
country’s leading facilities for analyzing drugs in biological materials and has extensive 
experience with various types of drug studies. 
 
Professor Olav Spigset (Medical Supervisor), St. Olavs Hospital 
 
Chief Physician Arne Helland, St. Olavs Hospital 
Namsos Hospital has a large bariatric surgery practice. The clinic will actively contribute to 
recruiting study participants by identifying suitable candidates/medications during the 
assessment process. 
 
Chief Physician Hallvard Græslie, Namsos Hospital 
Volvat Stokkan, Trondheim performs numerous sleeve gastrectomies. The clinic will 
actively contribute to recruiting study participants by identifying suitable 
candidates/medications during the assessment process. 
 
Coordinating Nurse Janicke Solberg 
The Research Unit at St. Olavs Hospital, along with the Center for Obesity Research, can 
assist in the practical execution of the study. 
 
Ethics and Safety 
Safety Assessment 
Aside from venous blood sampling, there are no interventions associated with project 
participation. The total volume of blood drawn is significantly less than what is considered 
safe in blood donation. A venous cannula (venflon) will be inserted to minimize the number 
of needle sticks for the participant. For participants who are difficult to cannulate, it may be 
necessary to allow them to leave the department for a few hours with the cannula in place. 
This could be relevant during 24-hour series where the participant sleeps at home. Participants 
will be well-informed about the risk of phlebitis and what actions to take if the cannula 
becomes dislodged. 
Study participants are covered by Norwegian patient injury insurance, as specified in the 
Patient Injury Act §1. 
Potential Benefits 
Regardless of the outcome, the study may benefit participants as the results will provide 
insights into whether the participant has an adequate dosage of the measured drugs post-
surgery. Upon completion of the last test, processed information will be shared with the 
participant through their general practitioner. If significant clinical changes are detected in 
essential medications early in the test series, the project’s medical supervisor will assess 
whether the general practitioner should be notified at an earlier stage. Normally, these patients 
undergo surgery without any focus on appropriate postoperative medication dosing. 

Results from the study will also benefit the patient groups as a whole once the information is 
published and made available. The findings will enable pharmacokinetic considerations for 
drugs to be integrated before choosing a surgical procedure, and will also increase attention 
on drug dosing in the postoperative phase. This can lead to health benefits for patients. 
On a societal level, potential benefits lie in whether this study could help prevent long-term 
complications caused by medication use. 
Ethics 
We find the study ethically acceptable as it involves minimal risk while the potential benefits 
may have significant clinical value. Privacy will be safeguarded by de-identifying sample 
results, keeping the code key separate from data, and storing data on a project server at St. 
Olavs Hospital. In the information letter, participants will consent to data sharing with other 
researchers, aligning with the principles of data pooling and research transparency. Such 
sharing (of anonymized data) will occur only upon specific request and with project leader 
approval. 
The study will be submitted for approval by the Regional Committee for Medical and Health 
Research Ethics (REK) and the Data Protection Officer for Research at St. Olavs Hospital. 
Dissemination 
We expect the study to generate a series of publications in international peer-reviewed 
journals. Preliminary and final findings will be presented at conferences. Additionally, 
findings will be integrated into education for both patients and healthcare professionals, with 
an emphasis on accessible scientific dissemination. 
Timeline 
This protocol essentially describes a series of parallel studies, where each drug tested 
represents a unique study group. Depending on the prevalence of the drug in the population, 
each group could consist of a single patient (for rare drugs) or up to twelve patients (for 
commonly used drugs). 
The study is planned to run over a ten-year period. Since recruitment will occur in parallel 
with the clinic’s patient evaluations, it is challenging to provide a precise forecast of progress. 
Should new analyses become available at the Department of Clinical Pharmacology, they may 
also be included in the study if relevant for the patient groups. The project itself is intended to 
continue for ten years. 
Funding 
The study has core funding from the Center for Obesity Research and the Department of 
Clinical Pharmacology but will seek additional funding. The most significant expenses will be 
the hiring of study nurses with experience in pharmacokinetic studies and training in Good 
Clinical Practice (GCP), as well as costs associated with drug analysis and enzyme 
genotyping. 

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prospective cohort: prevalence and associations with weight loss and health status in 
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