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

Study Overview
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Brief Summary
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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.

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

Conditions
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Drug Biotransformation, Membrane Transport

Intervention / Treatment
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* Drug: Codeine
* Drug: Midazolam
* Drug: Pravastatin
* Drug: Torsemide
* Drug: Talinolol
* Drug: Caffeine
* Drug: Metoprolol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Drug application<br>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<br>* Treatment period 2: 5 mg Codeine once<br>Drug: Midazolam<br>* Treatment period 1: 0.2 mg Midazolam 3x Treatment period 2: 1 mg Midazolam once<br>Drug: Pravastatin<br>* Treatment period 2: 5 mg Pravastatin once<br>Drug: Torsemide<br>* Treatment period 1: 2.5 mg Torsemide 3x Treatment period 2: 0.25 mg Torsemide once<br>Drug: Talinolol<br>* Treatment period 1: 50 mg Talinolol 3x Treatment period 2: 2.5 mg Talinolol once<br>Drug: Caffeine<br>* Treatment period 1: 50 mg Caffeine 3x<br>Drug: Metoprolol<br>* Treatment period 1: 5 mg Metoprolol 3x<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| plasma drug concentrations | 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. | up to 24 h after drug application | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK and metabolic ratios | 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. | up to 24 h after drug application | 
| variants in known genetic traits | New variants in known genetic traits are investigated and new genetic traits are identified. | up to 24 h after drug application | 
| design applicability | To evaluate the applicability of the repeated measure design for other, non drug-related genetic traits, such as blood coagulation pathways. | 54 months after study start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, heritability, drug membrane transport, drug biotransformation