Impact of Body Weight and Weight Loss on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers (COCKTAIL)

Impact of Body Weight, Low Calorie Diet and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors and Metabolic Biomarkers

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Obesity
• Intervention / Treatment: Procedure: Gastric bypass; Behavioral: 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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Norway
  • Vestfold
    • Tønsberg, Vestfold, Norway, 3103
      • HVestfold

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gastric bypass; 40 patients will undergo gastric bypass	Procedure: Gastric bypass; Weight loss surgery
Active Comparator: Very low calorie diet; 40 patients will undergo a very low calorie diet	Behavioral: Very low calorie diet; Non-surgical weight loss procedure
No Intervention: Gall bladder operation; 20 patients will be asked to undergo one pharmacokinetic study only, and then finish the study. They will not undergo any weight loss intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bioavailability of drugs (1)	Changes in absolute bioavailability (Area Under Curve - oral / Area Under Curve -intravenous) of midazolam after Gastric Bypass and Very Low Calorie Diet, respectively.	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
Bioavailability of drugs (2)	Changes in bioavailability (Area Under Curve - oral) of caffeine, losartan, digoxin, rosuvastatin and omeprazole after Gastric Bypass and Very Low Calorie Diet, respectively.	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

Collaborators and Investigators

• Sponsor: The Hospital of Vestfold
• Collaborators: University of Oslo; AstraZeneca
• Investigators: Principal Investigator: Jøran Hjelmesæth, Professor, The Hospital of Vestfold

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2015
• Primary Completion (Actual): June 1, 2019
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 24, 2015
• First Submitted That Met QC Criteria: March 8, 2015
• First Posted (Estimated): March 12, 2015

Study Record Updates

• Last Update Posted (Actual): October 2, 2024
• Last Update Submitted That Met QC Criteria: October 1, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Body Weight
• Other Study ID Numbers: 2013-2379

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO