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

Gastrointestinal Hormones Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02507167
• Other study ID #: CCK8/RIFA-2012
• Status: Completed
• Phase: Phase 1
• First received: July 22, 2015
• Last updated: July 22, 2015
• Start date: November 2012
• Est. completion date: December 2014

Study information

• Verified date: July 2015
• Source: University Medicine Greifswald
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: December 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

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 Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Gastrointestinal Hormones

Intervention

Dietary Supplement:
• mixed meal
250 ml Fortimel compact (chocolate)

Drug:
• Rifampin
oral rifampin administration (600 mg EREMFAT®)

Locations

Country	Name	City	State
Germany	Department of Clinical Pharmacology	Greifswald

Sponsors (1)

Lead Sponsor	Collaborator
University Medicine Greifswald

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	No
Other	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	No
Other	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	No
Other	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	No
Other	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	No
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No