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

Overview[ - collapse ][ - ]

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.
ConditionDrug Biotransformation
Membrane Transport
InterventionDrug: Codeine
Drug: Midazolam
Drug: Pravastatin
Drug: Torsemide
Drug: Talinolol
Drug: Caffeine
Drug: Metoprolol
PhasePhase 1
SponsorInstitut fuer anwendungsorientierte Forschung und klinische Studien GmbH
Responsible PartyInstitut fuer anwendungsorientierte Forschung und klinische Studien GmbH
ClinicalTrials.gov IdentifierNCT01845194
First ReceivedApril 25, 2013
Last UpdatedApril 17, 2014
Last verifiedApril 2014

Tracking Information[ + expand ][ + ]

First Received DateApril 25, 2013
Last Updated DateApril 17, 2014
Start DateDecember 2009
Estimated Primary Completion DateOctober 2013
Current Primary Outcome Measuresplasma 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.
Current 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.

Descriptive Information[ + expand ][ + ]

Brief TitleRepeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics
Official TitleOpen Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics (TWINS II)
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.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 1
Study DesignEndpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science
Condition
  • Drug Biotransformation
  • Membrane Transport
InterventionDrug: 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
Study Arm (s)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

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment117
Estimated Completion DateOctober 2013
Estimated Primary Completion DateOctober 2013
Eligibility 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
GenderBoth
Ages18 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsNot Provided
Location CountriesGermany

Administrative Information[ + expand ][ + ]

NCT Number NCT01845194
Other Study ID NumbersTWINS-II-v1.9
Has Data Monitoring CommitteeNo
Information Provided ByInstitut fuer anwendungsorientierte Forschung und klinische Studien GmbH
Study SponsorInstitut fuer anwendungsorientierte Forschung und klinische Studien GmbH
CollaboratorsNot Provided
Investigators Study Chair: Jürgen Brockmöller, Prof. Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany
Verification DateApril 2014

Locations[ + expand ][ + ]

Dept. of Clinical Pharmacology, Georg-August-University of Goettingen
Goettingen, Germany, 37075