Clinical trial NCT02386917: Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
Official title: Impact of Body Weight, Low Calorie Diet and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Obesity
Lead sponsor: The Hospital of Vestfold
Sponsor class: OTHER
Collaborators: name: University of Oslo
name: AstraZeneca
First posted: 2015-03-12
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Drug bioavailability and disposition vary according to body weight and weight loss after bariatric surgery. This study evaluates the impact of body weight and weight loss on the pharmacokinetics of various probe drugs, and compares these effects in three groups of patients receiving either a gall bladder operation, gastric bypass or a very low calorie diet.

Detailed description: This study aims to

1. to investigate the relationship between body composition and the liver/intestine activity and expression of proteins (drug metabolizing enzymes, transporters and regulatory factors) important for drug bioavailability and disposition in the range from normal to morbid obesity (the combined gastric bypass and cholecystectomy groups) at baseline.
2. to compare the short-term (6-week) and long-term (2 years) effect of gastric bypass (GBP) and a very low calorie diet (VLCD) (matched weight loss) on bioavailability and pharmacokinetics of probe drugs (caffeine, omeprazole, digoxin, midazolam, rosuvastatin, losartan) and biomarkers (and adjoining protein expressions) for cytochrome P450 (CYP)1A2, CYP2C9, CYP2C19, CYP3A, P-glycoprotein (gp) and organic anion-transporting polypeptide (OATP)1B1.
3. to compare the 3 study groups (GBP, VLCD and cholecystectomy) at baseline with respect to body composition, cardiovascular risk factors and metabolic biomarkers.
4. to compare the short-term (6-week) changes in glucose metabolism, blood pressure, blood lipids and body composition of matched weight loss and long-term effects (2 year) on body composition, cardiovascular risk factors and metabolic biomarkers, between the GBP and VLCD groups.

Eligibility criteria: Inclusion Criteria:

1. Patients scheduled for GBP surgery or VLCD intervention for obesity as well as patients scheduled for cholecystectomy.
2. BMI ≥ 18.5 kg/m2
3. Able and willing to donate biopsies (as specified in the protocol) and for the GBP and VLCD patients also willing to perform follow-up 24 hour PK-investigations and other assessments as required by the clinical study protocol
4. Stable body weight (\< 5 kg self reported weight change) during the last 3 months before inclusion.
5. Signed informed consent.

Exclusion Criteria:

* Concomitant treatment with drugs (according to available literature, appendix 3) and/or other factors that may influence the cocktail drug pharmacokinetics such as grapefruit juice, Seville oranges, Pomelo juice, St. Johns wort, tobacco and coffee/tea in close approximation to the investigations.
* Bradyarrhythmia, Wolff-Parkinson-White (WPW)-syndrome, atrioventricular block 2-3.
* Electrolyte disturbances (particularly hypokalemia or hypomagnesemia).
* Renal impairment: eGFR \< 30 mL/min.
* Blood donations the last 4 months.
* Previous bariatric or upper gastrointestinal surgery.
* Diabetic patients treated with glitazones, insulin or sulfonylureas.
* Pregnancy (checked with HCG in urine at screening) and breast-feeding mothers.
* Known hypersensitivity (including allergy) to drugs included in the cocktail and/or local anesthesia.
* Anticoagulants with associated risk in combination with biopsies.
* Non-compliance with regards to visits and/or diet.

Primary outcomes:
measure: Bioavailability of drugs (1)
timeFrame: 0 hours and 0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 4.5, 5, 5.5, 6, 8, 10*, 12*, 23 and 24 hours following administration
measure: Bioavailability of drugs (2)
timeFrame: 0 hours and 0.25, 0.5, 1, 1.5, 2, 3, 4, 4.25, 4.5, 5, 5.5, 6, 8, 10*, 12*, 23 and 24 hours following administration
Secondary outcomes:
Other outcomes:
Locations:
city: Tønsberg
country: Norway
facility: HVestfold
state: Vestfold
Study officials:
affiliation: The Hospital of Vestfold
name: Jøran Hjelmesæth, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eide Kvitne K, Hole K, Krogstad V, Wollmann BM, Wegler C, Johnson LK, Hertel JK, Artursson P, Karlsson C, Andersson S, Andersson TB, Sandbu R, Hjelmesaeth J, Skovlund E, Christensen H, Jansson-Lofmark R, Asberg A, Molden E, Robertsen I. Correlations between 4beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. Eur J Clin Pharmacol. 2022 Aug;78(8):1289-1299. doi: 10.1007/s00228-022-03336-9. Epub 2022 Jun 1.
citation: Hjelmesaeth J, Asberg A, Andersson S, Sandbu R, Robertsen I, Johnson LK, Angeles PC, Hertel JK, Skovlund E, Heijer M, Ek AL, Krogstad V, Karlsen TI, Christensen H, Andersson TB, Karlsson C. Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL). BMJ Open. 2018 May 29;8(5):e021878. doi: 10.1136/bmjopen-2018-021878.