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)

• Published in: BMJ open Vol. 8; no. 5; p. e021878
• Main Authors: Hjelmesæth, Jøran, Åsberg, Anders, Andersson, Shalini, Sandbu, Rune, Robertsen, Ida, Johnson, Line Kristin, Angeles, Philip Carlo, Hertel, Jens Kristoffer, Skovlund, Eva, Heijer, Maria, Ek, Anna-Lena, Krogstad, Veronica, Karlsen, Tor-Ivar, Christensen, Hege, Andersson, Tommy B, Karlsson, Cecilia
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01-05-2018; BMJ Publishing Group
• Subjects: atorvastatin; bariatric; beta-cell function; Bioavailability; Biological Availability; Biomarkers; Body Composition; Caloric Restriction - adverse effects; Cancer; Cardiovascular Diseases - etiology; Cholecystectomy; Clinical Trials as Topic; Diabetes; Drug dosages; Enzymes; Female; Gastric Bypass - adverse effects; Gastric Bypass - methods; Gastrointestinal surgery; General & Internal Medicine; Heart surgery; Humans; inflammation; Kirurgi; Linear Models; Male; Medicin och hälsovetenskap; Metabolism; morbidly obese-patients; Norway; Obesity; Obesity, Morbid - therapy; oral bioavailability; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology and Therapeutics; Protein expression; Proteins; Quality of life; Quantitative psychology; Questionnaires; Risk Factors; Short term; Surgery; systemic exposure; Tertiary Care Centers; Weight control; Weight Loss; Norway; clinical pharmacology; basic sciences; cardiology
• ISSN: 2044-6055; 2044-6055
• DOI: 10.1136/bmjopen-2018-021878

IntroductionRoux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups.Methods and analysisThis open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUCoral/AUCiv) of midazolam (CYP3A4 probe), systemic exposure (AUCoral) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers.Ethics and disseminationThe COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants.Trial registration number NCT02386917.