Repeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics

Sponsor

Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH (Other)

Overall Status

Completed

CT.gov ID

NCT01845194

Collaborator

(none)

117

Enrollment

Location

Arm

Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This human pharmacokinetic study investigates, whether processes of drug metabolism and transport are determined by genetic or hereditary factors. Therefore, approved drugs are applied to twins and metabolism and transport processes are investigated.

Condition or Disease	Intervention/Treatment	Phase
Drug Biotransformation Membrane Transport	Drug: Codeine Drug: Midazolam Drug: Pravastatin Drug: Torsemide Drug: Talinolol Drug: Caffeine Drug: Metoprolol	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

117 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Open Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics (TWINS II)

Study Start Date :

Dec 1, 2009

Actual Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Drug application Two treatment periods: Treatment period 1: three sequential oral and i.v. doses of 5 mg Metoprolol, 50 mg Talinolol, 2.5 mg Torsemide, 0.2 mg Midazolam and 50 mg Caffeine. At least 1 week of wash out between drug application Treatment period 2: combined application of a single oral dose of 2.5 mg Talinolol, 0.25 mg Torsemide, 5 mg Pravastatin, 1 mg Midazolam and 5 mg Codeine. Treatment period 2 may take place after or before treatment period 1 with a time interval of at least 1 week	Drug: Codeine Treatment period 2: 5 mg Codeine once Drug: Midazolam Treatment period 1: 0.2 mg Midazolam 3x Treatment period 2: 1 mg Midazolam once Drug: Pravastatin Treatment period 2: 5 mg Pravastatin once Drug: Torsemide Treatment period 1: 2.5 mg Torsemide 3x Treatment period 2: 0.25 mg Torsemide once Drug: Talinolol Treatment period 1: 50 mg Talinolol 3x Treatment period 2: 2.5 mg Talinolol once Drug: Caffeine Treatment period 1: 50 mg Caffeine 3x Drug: Metoprolol Treatment period 1: 5 mg Metoprolol 3x

Arm

Intervention/Treatment

Experimental: Drug application

Two treatment periods: Treatment period 1: three sequential oral and i.v. doses of 5 mg Metoprolol, 50 mg Talinolol, 2.5 mg Torsemide, 0.2 mg Midazolam and 50 mg Caffeine. At least 1 week of wash out between drug application Treatment period 2: combined application of a single oral dose of 2.5 mg Talinolol, 0.25 mg Torsemide, 5 mg Pravastatin, 1 mg Midazolam and 5 mg Codeine. Treatment period 2 may take place after or before treatment period 1 with a time interval of at least 1 week

Drug: Codeine

Treatment period 2: 5 mg Codeine once

Drug: Midazolam

Treatment period 1: 0.2 mg Midazolam 3x Treatment period 2: 1 mg Midazolam once

Drug: Pravastatin

Treatment period 2: 5 mg Pravastatin once

Drug: Torsemide

Treatment period 1: 2.5 mg Torsemide 3x Treatment period 2: 0.25 mg Torsemide once

Drug: Talinolol

Treatment period 1: 50 mg Talinolol 3x Treatment period 2: 2.5 mg Talinolol once

Drug: Caffeine

Treatment period 1: 50 mg Caffeine 3x

Drug: Metoprolol

Treatment period 1: 5 mg Metoprolol 3x

Outcome Measures

Primary Outcome Measures

plasma drug concentrations [up to 24 h after drug application]
Up to 8 (± 60 min.) hour after each application of combined drugs (treatment period 1 and treatment period 2) blood and urine collection is continuously performed and drug concentrations as specified in the sections "study arms" and "interventions" are measured. This is repeated once 24 hours after each drug application.

Secondary Outcome Measures

PK and metabolic ratios [up to 24 h after drug application]
PK and metabolic ratios (MR, ratio between parent compound and metabolite) of the test substrates as specified in the sections "study arms" and "interventions" are measured.
variants in known genetic traits [up to 24 h after drug application]
New variants in known genetic traits are investigated and new genetic traits are identified.
design applicability [54 months after study start]
To evaluate the applicability of the repeated measure design for other, non drug-related genetic traits, such as blood coagulation pathways.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Written informed consent obtained prior to study entry including informed consent for genetic research
Both genders (male and female)
Healthy adults aged ≥18 to < 65 years
Body weight of subjects of both genders not less than 50 kg and not more than 120 kg. BMI not less than 18 kg/m² and not greater than 33 kg/m²
Willingness to meet the study instructions and to co-operate with the study personal
No clinically relevant pathological findings in any of the investigations at the Screening visit. Minor deviations of laboratory values from the normal range may be accepted, if judged by the investigator to have no clinical relevance
Female subjects will only be included if they have negative serum pregnancy test during screening and the willingness not to become pregnant during the entire study period by practicing reliable methods of contraception as specified in the respective protocol section.
Dizygotic twins will only be included if both siblings are of the same gender, either male or female and triplets, quadruplets or other multiplets if at least two siblings are of the same gender
Smokers will only be included if both siblings are smoking to a similar extend (+/- 10 cigarettes per day)

Exclusion Criteria:

Involvement in the planning and conduct of the study (applies to staff directly employed at the study site / department)
Participation in a clinical study during the last 30 days or use of any other investigational or non-registered drug or vaccine during the study period or within 30 days preceding the first dose of study drugs
Blood, plasma or thrombozyte donation during the last 30 days prior to application of the test drugs
Age < 18 years or > 65 years
Known pregnancy or lactation period
Any relevant pathological findings in any of the investigations at the screening visit including significant abnormalities as result of the medical-screening-laboratory-analysis, especially of the liver and kidney related parameters.
Any disease affecting liver or kidney or impairment of the liver or kidney-function
Any cardiac disease in which use of beta-blockers or caffeine might be contraindicated.
Bronchogenic asthma requiring constant drug treatment (stages 2 to 4 asthma)
Known Raynaud's syndrome
Any major acute disease or fever (Temp. > 37.5 C)
Any major gastrointestinal disease and any gastrointestinal disorder that is expected to significantly interfere with the pharmacokinetics of the study drug
Gastrointestinal surgery which may interfere with the pharmacokinetics of the study drug (except appendectomy or herniotomy)
Taking any medication within 7 days before or during the trial with the following exceptions: Single doses of mild analgesics (e.g. aspirin, paracetamol, ibuprofen) may have been taken except for the time from 6 hours prior to taking the test drug until 24 hours after taking the test drug. Oral contraceptive drug used will be documented but will not be an exclusion criterion. Other medication might be allowed on single case basis if considered necessary for the subject's safety and well-being.
History of alcohol and/or drug addiction and/or any abusive use of medicaments and/or positive drug screen
Any other findings that could compromise the safety of the participant or the quality of the study-results
History of severe hypersensitivity reactions and anaphylaxis
If hypersensitivity or allergic reactions to one of the IMPs is known so enrolment is possible but application of the concerned IMP must not be allowed in all siblings (e.g. allergy to sulphonamide prohibits specifically the application of torsemide)
Clinically significant diseases as judged by the investigator
Body temperature > 37.5°C prior to drug application
Known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C
Inability or unwillingness to avoid any intake of alcohol from 48h prior to until 72hours after IMP application
Pregnancy (positive pregnancy test during screening and/or treatment)
Lactation or unreliable contraception in female subjects with child-bearing potential
Inability or unwillingness to provide informed consent and to abide by the requirements of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dept. of Clinical Pharmacology, Georg-August-University of Goettingen	Goettingen		Germany	37075

Sponsors and Collaborators

Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH

Investigators

Study Chair: Jürgen Brockmöller, Prof., Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany