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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
ClinicalTrials.gov Identifier:
NCT01845194
First received: April 25, 2013
Last updated: April 17, 2014
Last verified: April 2014
  Purpose

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 Intervention Phase
Drug Biotransformation
Membrane Transport
Drug: Codeine
Drug: Midazolam
Drug: Pravastatin
Drug: Torsemide
Drug: Talinolol
Drug: Caffeine
Drug: Metoprolol
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: 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)

Resource links provided by NLM:


Further study details as provided by Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH:

Primary Outcome Measures:
  • plasma drug concentrations [ Time Frame: up to 24 h after drug application ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 24 h after drug application ] [ Designated as safety issue: No ]
    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 [ Time Frame: up to 24 h after drug application ] [ Designated as safety issue: No ]
    New variants in known genetic traits are investigated and new genetic traits are identified.

  • design applicability [ Time Frame: 54 months after study start ] [ Designated as safety issue: No ]
    To evaluate the applicability of the repeated measure design for other, non drug-related genetic traits, such as blood coagulation pathways.


Enrollment: 117
Study Start Date: December 2009
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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


  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01845194

Locations
Germany
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
  More Information

No publications provided

Responsible Party: Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
ClinicalTrials.gov Identifier: NCT01845194     History of Changes
Other Study ID Numbers: TWINS-II-v1.9
Study First Received: April 25, 2013
Last Updated: April 17, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH:
pharmacokinetic
heritability
drug membrane transport
drug biotransformation

Additional relevant MeSH terms:
Midazolam
Codeine
Caffeine
Metoprolol
Metoprolol succinate
Talinolol
Torsemide
Pravastatin
Adjuvants, Anesthesia
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Arrhythmia Agents
Cardiovascular Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents

ClinicalTrials.gov processed this record on October 01, 2014