The effect of a gastric bypass surgery on the absorption of acetylsalicylic
acid and omeprazole after ingestion.

Rationale:

Roux-en-Y Bariatric (RYGB) surgery is asuccessful approach to morbid
obesity. In this procedure, the stomach is reducedto a small 'gastric
pouch’. The duodenum is bypassed by connecting the jejunumthis gastric
pouch. The duodenum is then connected to a later part of thejejunum to
ensure the passage of bile salts and pancreatic enzymes.



After oral intake, food and drugs firstpass the created gastric pouch
before passing directly into the shortenedjejunum. Literature shows that
this results in problems regarding vitamin andnutrient absorption. In
contrast, little literature is available on theabsorption of orally
administered drugs. The available literature consistsmainly of case
reports or small studies. Several authors have tried to build amodel in
which the change in absorption after RYGB surgery can be
predicted,unfortunately without success. As there is no model available
for predictingchanges in drug absorption after the surgery, research is
necessary for drugs frequentlyused in this population.

We investigated the medication use of 115 patients in our center to
obtain insight into the types of medicationfrequently used by this group
of patients. Results showed that aspirin andomeprazole are two commonly
used drugs.

In order to prevent arterial thromboticdisease in high-risk patients
such as our population, treatment withacetylsalicylic acid is commonly
prescribed for life-long use. A dosage of75-150 mg is proven to be an
efficient dose in preventing mortality, myocardialinfarction or stroke.
This is not proven for a dose of less than 75 mg per day,except for
stroke. Acetylsalicylic acid is mainly absorbed in the acidicenvironment
of the stomach and partly in the duodenum. Changes in pH andgastric
volume after RYGB surgery could affect the extent of absorption of
ASA.Until now, no data are available on absorption of ASA in RYGB
surgery patients.Reduced absorption of aspirin could have long term
implications for theeffectiveness in the prevention of thromboembolic
events and death. For thisreason, it is important to investigate the
impact of RYGB surgery on theabsorption of acetylsalicylic acid. We
hypothesize that the absorption ofacetylsalicylic acid after oral
administration will be reduced by RYGB surgery.

As a proton pump inhibitor, omeprazoleinhibits the production of stomach
acid, resulting in a less acidic stomach. Omeprazoleis prescribed after
RYGB operation in a dosage of 20 mg twice daily to reducethe chance of
development of anastomotic ulcerations and leakage. Omeprazole isan acid
labile substance and is therefore always administered with an
entericcoating. After passing the stomach this coating dissolves and
omeprazole israpidly absorbed in the small intestine. Due to a higher pH
in the stomachafter RYGB surgery, the enteric coating around the tablet
can disappear fasterand omeprazole could be more rapidly absorbed. An in
vitro experiment indeedshowed an accelerated uptake of omeprazole after
the procedure, with no effecton the overall absorption of omeprazole. It
is of great importance that theabsorption of omeprazole is sufficient to
prevent complications after RYGBsurgery. For this reason we want to
confirm previous results and investigatethe influence of RYGB surgery on
the absorption of omeprazole in this study Wehypothesize that the
absorption of omeprazole after oral administration will befaster but
equivalent after RYGB surgery.



Objective:

The primary objective of the ERY-PAOstudy is to investigate the
pharmacokinetics of acetylsalicylic acid (ASA) and omeprazolein morbidly
obese subjects before and after RYGB surgery and to compare thesedata to
study if there aredifferences in pharmacokinetics due to thisprocedure.



Study design:

Single centre, longitudinal open labelrepeated measures study.



Study population:

The study population will consist ofmorbidly obese subjects approved by
the Dutch Obesity Clinic (NOK) West to
undergo RYGB surgery. Approximately 350patients per year are approved
for this surgery. Approximately 80% of the patientsapproved for surgery
are female; mean age is 40 to 45 years. Patients aremostly of Caucasian,
Hindu or African ethnicity. The study group consist ofhighly motivated
study subjects. In order to get approved for surgery a longtrajectory,
including guidance in diet, physical exercise and
psychosocialcounselling has been completed.



Intervention:

The subjects will be asked to takeomeprazole 20 mg for a total duration
of 2 weeks (day 1 * 14) before the RYGB surgery. After surgery,
administration of omeprazole 20 mg twice daily is standard carefor the
duration of 6 months. In addition, the subjects will be asked to take
asingle dose of ASA 80 mg on 2 ‘test’ days: day 7 of omeprazole
treatment beforesurgery, and day 7 of study medication omeprazole
treatment after RYGB surgery.Test days will be planned at least 2 weeks
before and 6 weeks after thesurgery. During the intervention periods,
the subjects will be asked to fillout a medication diary to check
adherence.



Primary studyparameters/outcome of the study:

The primary study parameters are drugblood concentrations on the
selected test days and times: 0 (before intake of thedrugs), 30 minutes
after intake, 1 hour, 2 hours and 4 hours after intake. Withthese
concentrations the following pharmacokinetic parameters will be
determined:Time to peak concentration (Tmax), peak concentration (Cmax),
area under thecurve (AUC), and half-life (t ½) of salicylic acid and
omeprazole.

Roux-en-Y Bariatric (RYGB) surgery is a successful approach to morbid obesity. In this procedure, the stomach is reduced to a small 'gastric pouch' . The duodenum is bypassed by connecting the jejunum this gastric pouch. The duodenum is then connected to a later part of the jejunum to ensure the passage of bile salts and pancreatic enzymes. After oral intake, food and drugs first pass the created gastric pouch before passing directly into the shortened jejunum. Literature shows that this results in problems regarding vitamin and nutrient absorption. In contrast, little literature is available on the absorption of orally administered drugs. The available literature consists mainly of case reports or small studies. Several authors have tried to build a model in which the change in absorption after RYGB surgery can be predicted, unfortunately without success. As there is no model available for predicting changes in drug absorption after the surgery, research is necessary for drugs frequently used in this population. We investigated the medication use of 115 patients in our center to obtain insight into the types of medication frequently used by this group of patients. Results showed that aspirin and omeprazole are two commonly used drugs. In order to prevent arterial thrombotic disease in high-risk patients such as our population, treatment with acetylsalicylic acid is commonly prescribed for life-long use. A dosage of 75-150 mg is proven to be an efficient dose in preventing mortality, myocardial infarction or stroke. This is not proven for a dose of less than 75 mg per day, except for stroke. Acetylsalicylic acid is mainly absorbed in the acidic environment of the stomach and partly in the duodenum. Changes in pH and gastric volume after RYGB surgery could affect the extent of absorption of ASA. Until now, no data are available on absorption of ASA in RYGB surgery patients. Reduced absorption of aspirin could have long term implications for the effectiveness in the prevention of thromboembolic events and death. For this reason, it is important to investigate the impact of RYGB on the absorption of acetylsalicylic acid. We hypothesize that the absorption of acetylsalicylic acid after oral administration will be reduced by RYGB surgery. As a proton pump inhibitor, omeprazole inhibits the production of stomach acid, resulting in a less acidic stomach. Omeprazole is prescribed after RYGB operation in a dosage of 20 mg twice daily to reduce the chance of development of anastomotic ulcerations and leakage. Omeprazole is an acid labile substance and is therefore always administered with an enteric coating. After passing the stomach this coating dissolves and omeprazole is rapidly absorbed in the small intestine. Due to a higher pH in the stomach after RYGB surgery, the enteric coating around the tablet can disappear faster and omeprazole could be more rapidly absorbed. An in vitro experiment indeed showed an accelerated uptake of omeprazole after the procedure, with no effect on the overall absorption of omeprazole. It is of great importance that the absorption of omeprazole is sufficient to prevent complications after RYGB surgery. For this reason we want to confirm previous results and investigate the influence of RYGB surgery on the absorption of omeprazole in this study We hypothesize that the absorption of omeprazole after oral administration will be faster but equivalent after RYGB surgery.

Test days will be mostly clustered and will take place before and after the surgery.

Blood sampling will be solely for study purposes and will be done on test day 1 and 2 in intervals during a period of 4 hours. Volumes of 4 ml are required for every analysis on drug concentrations. For genotyping, one sample with a volume of 7 ml is required.

In total, this results in 27 ml blood sample on test day 1 and 20 ml blood sample on test day 2.
Blood sampling will be done by venapunction on the designated test times by qualified health care professionals. Body length will be registered at inclusion. Determination of body weight and body fat percentage is part of the regular pre and aftercare for RYGB surgery. For the study the most recently measured weight and fat percentage compared with the test day will be registered. Subjects will be asked to fill out a diary during the intervention periods to assess adherence to the study medication and use of other medication.

The subjects will be asked to take omeprazole 20 mg for a total duration of 2 weeks (day 1 – 14) before the RYGB surgery. After surgery, administration of omeprazole 20 mg twice daily is standard care for the duration of 6 months. In addition, the subjects will be asked to take a single dose of ASA 80 mg on 2 ‘test’ days: day 7 of omeprazole treatment before surgery, and day 7 of study medication omeprazole treatment after RYGB surgery. Test days will be planned at least 2 weeks before and 6 weeks after the surgery. During the intervention periods, the subjects will be asked to fill out a medication diary to check adherence.