Clinical trial NCT02507167: Impact of Two Genetic Variants of OATP1B3 or MRP2 or Rifampin on Systemic Disposition and Biological Efficacy of CCK-8
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Gastrointestinal Hormones
Lead sponsor: University Medicine Greifswald
Sponsor class: OTHER
First posted: 2015-07-23
Enrollment: 19
Sex: MALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: CCK-8
timeFrame: 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 outcomes:
measure: GLP-1
timeFrame: 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
measure: GIP
timeFrame: 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
measure: glucagon
timeFrame: 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
measure: glucose
timeFrame: 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
measure: potassium
timeFrame: 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
measure: C-peptide
timeFrame: 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
measure: insulin
timeFrame: 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal
Other outcomes:
measure: 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)
timeFrame: 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
measure: area under the curve AUC from zero to 4 h (AUC0-4h) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)
timeFrame: 3 h 15 min up to 2 h 15 min, 1.5, 1 h before and 5 min, 1, 2 h after mixed meal
measure: maximal concentration (Cmax) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)
timeFrame: 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
measure: time point of maximal concentration (tmax) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)
timeFrame: 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
measure: terminal half-life (t1/2) of rifampin and DAc-RIF (25-O-desacetyl-rifampin)
timeFrame: 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
Locations:
city: Greifswald
country: Germany
facility: Department of Clinical Pharmacology
Study officials:
affiliation: Department of Clinical Pharmacology
name: Werner Siegmund, Prof
role: PRINCIPAL_INVESTIGATOR
References: