Impact of Two Genetic Variants of OATP1B3 or MRP2 or Rifampin on Systemic Disposition and Biological Efficacy of CCK-8

Impact of Two Genetic Variants of OATP 1B3 or MRP 2 or Rifampin Mediated Transporter Inhibition on Systemic Disposition and Biological Efficacy of CCK-8 in 36 Healthy Male Individuals

The purpose of this study is to evaluate the impact of genetic variants of OATP 1B3 or MRP 2 on the systemic disposition of endogenously formed CCK-8 and to determine the influence of a single-dose of the transporter inhibitor rifampin (600 mg) on the systemic disposition of endogenously formed CCK-8. Endogenous CCK-8 secretion will be induced by a single-dose standardized liquid mixed meal.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Hormones
• Intervention / Treatment: Dietary supplement: mixed meal; Drug: Rifampin

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Greifswald, Germany, 17489
    • Department of Clinical Pharmacology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• age: 18-45 years
• sex: male
• 12 subjects being homozygote wild-type carriers of OATP 1B3 (c.SLCO 1B3 699 AA and c.SLCO 1B3 334 GG) and MRP 2
• 12 subjects being homozygotes of the MRP 2 variants (genetic loss of function) and homozygote wild-type carriers of OATP 1B3
• 12 subjects being homozygotes of the OATP 1B3 variants (c.SLCO 1B3 699 GG and c.SLCO 1B3 334 TT) and homozygotes wild-type carriers of MRP 2
• BMI: ≥ 19 kg/m2 and ≤ 27 kg/m2
• good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which will be judged by the clinical investigator not to differ in a clinical relevant way from the healthy state
• written informed consent given by the volunteer after being provided with detailed information (both, verbally and written) about the nature, risks, and scope of the clinical trial as well as the expected desirable and adverse effects of the drug

Exclusion Criteria:

• hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication
• gastrointestinal diseases and/or pathological findings (e.g. stenoses), which might interfere with pharmacokinetics and pharmacodynamics of the study medication
• subjects with existing dysfunction in regulation of glucose metabolism, e.g. deficiency of glucose-6-phosphate dehydrogenase (Glc-6-P DHG) and/ or pathological findings
• subjects with alcohol and/ or drug dependence and a alcohol consumption more than 20 g alcohol/ day
• excessive smoking (more than 10 cigarettes or equivalents/ day)
• subjects with positive finding of HBsAG, HIV and/ or drugs
• subjects being on a diet (inclusive special or uniform nutritional habits, e.g. vegetarians or undercaloric diet)
• strong coffee and/ or tea consumption (≥ 1 liter a day)
• subjects suspected or known not to follow instructions
• subjects who are unable to understand written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study
• subjects liable to orthostatic dysregulation, fainting, or blackout
• subjects who took part in other clinical trials in the last 3 months (blocking time due to another clinical trial with investigational products)
• acute illness less than 14 d in the past
• blood donation within the last 3 months
• any medication within 4 weeks prior to the intended first administration of the study medication which might influence functions of the gastrointestinal tract (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists, proton pump inhibitors, anticholinergics)
• any other medication within 2 weeks prior to the first administration of the study medication or less than 10-time the half-live of the respective drug
• intake of grapefruit containing food or beverages and poppy seeds containing products 14 d prior to the first drug administration until the last blood sampling of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: mixed meal	Dietary supplement: mixed meal; 250 ml Fortimel compact (chocolate)
Active Comparator: mixed meal 2 h after single dose rifampin (600 mg)	Dietary supplement: mixed meal; 250 ml Fortimel compact (chocolate); Drug: Rifampin; oral rifampin administration (600 mg EREMFAT®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CCK-8	Cholecystokinin amino acid 8 concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GLP-1	Glucagon-like peptide-1 concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal
GIP	Gastric inhibitory polypeptide concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal
glucagon	glucagon concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal
glucose	glucose concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
potassium	potassium concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
C-peptide	connecting peptide concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
insulin	insulin concentration in blood plasma	3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal

Other Outcome Measures

Outcome Measure	Time Frame
area under the curve AUC from zero to the last sampling time above the limit of quantitation (AUC0-t) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)	3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2, 3, 4, 6, 8, 10 and 14 h after mixed meal
area under the curve AUC from zero to 4 h (AUC0-4h) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)	3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2 h after mixed meal
maximal concentration (Cmax) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)	3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2, 3, 4, 6, 8, 10 and 14 h after mixed meal
time point of maximal concentration (tmax) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)	3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2, 3, 4, 6, 8, 10 and 14 h after mixed meal
terminal half-life (t1/2) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)	3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2, 3, 4, 6, 8, 10 and 14 h after mixed meal

Collaborators and Investigators

• Sponsor: University Medicine Greifswald

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: July 22, 2015
• First Submitted That Met QC Criteria: July 22, 2015
• First Posted (Estimate): July 23, 2015

Study Record Updates

• Last Update Posted (Estimate): July 23, 2015
• Last Update Submitted That Met QC Criteria: July 22, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin
• Other Study ID Numbers: CCK8/RIFA-2012