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

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

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.

Study Overview

• Status: Completed
• Conditions: Membrane Transport; Drug Biotransformation
• Intervention / Treatment: Drug: Codeine; Drug: Midazolam; Drug: Pravastatin; Drug: Torsemide; Drug: Talinolol; Drug: Caffeine; Drug: Metoprolol

• Study Type: Interventional
• Enrollment (Actual): 117
• Phase: Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: 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

Publications and helpful links

General Publications

• Matthaei J, Bonat WH, Kerb R, Tzvetkov MV, Strube J, Brunke S, Sachse-Seeboth C, Sehrt D, Hofmann U, von Bornemann Hjelmborg J, Schwab M, Brockmoller J. Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans. Front Genet. 2020 Aug 21;11:944. doi: 10.3389/fgene.2020.00944. eCollection 2020.
• Matthaei J, Tzvetkov MV, Gal V, Sachse-Seeboth C, Sehrt D, Hjelmborg JB, Hofmann U, Schwab M, Kerb R, Brockmoller J. Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters. Genome Med. 2016 Nov 8;8(1):119. doi: 10.1186/s13073-016-0372-2.
• Matthaei J, Brockmoller J, Tzvetkov MV, Sehrt D, Sachse-Seeboth C, Hjelmborg JB, Moller S, Halekoh U, Hofmann U, Schwab M, Kerb R. Heritability of metoprolol and torsemide pharmacokinetics. Clin Pharmacol Ther. 2015 Dec;98(6):611-21. doi: 10.1002/cpt.258. Epub 2015 Oct 19.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): October 1, 2013
• Study Completion (ACTUAL): October 1, 2013

Study Registration Dates

• First Submitted: April 25, 2013
• First Submitted That Met QC Criteria: April 29, 2013
• First Posted (ESTIMATE): May 3, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): April 21, 2014
• Last Update Submitted That Met QC Criteria: April 17, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: pharmacokinetic; heritability; drug membrane transport; drug biotransformation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Purinergic Antagonists; Purinergic Agents; Antimetabolites; Natriuretic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Analgesics, Opioid; Narcotics; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Diuretics; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Antitussive Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Sodium Potassium Chloride Symporter Inhibitors; Midazolam; Pravastatin; Metoprolol; Caffeine; Codeine; Talinolol; Torsemide
• Other Study ID Numbers: TWINS-II-v1.9