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

NCT01845194 | Completed Phase 1

• 1 other identifier: TWINS-II-v1.9
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 1

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.

Conditions

Drug Biotransformation; Membrane Transport

Keywords

pharmacokinetic; heritability; drug membrane transport; drug biotransformation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• PK and metabolic ratios

  up to 24 h after drug application

• variants in known genetic traits

  up to 24 h after drug application

• design applicability

  54 months after study start

Study Arms (1)

Drug application

EXPERIMENTAL

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; Drug: Midazolam; Drug: Pravastatin; Drug: Torsemide; Drug: Talinolol; Drug: Caffeine; Drug: Metoprolol

Interventions

Codeine DRUG

Treatment period 2: 5 mg Codeine once

Drug application

Midazolam DRUG

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

Drug application

Pravastatin DRUG

Treatment period 2: 5 mg Pravastatin once

Drug application

Torsemide DRUG

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

Drug application

Talinolol DRUG

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

Drug application

Caffeine DRUG

Treatment period 1: 50 mg Caffeine 3x

Drug application

Metoprolol DRUG

Treatment period 1: 5 mg Metoprolol 3x

Drug application

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH: lead

Study Sites (1)

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

Göttingen, 37075, Germany

Location

Related Publications (3)

• 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.

  PMID: 32973880 DERIVED

• 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.

  PMID: 27825374 DERIVED

• 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.

  PMID: 26344676 DERIVED

MeSH Terms

Interventions

Codeine; Midazolam; Pravastatin; Torsemide; talinolol; Caffeine; Metoprolol

Intervention Hierarchy (Ancestors)

Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Naphthalenes; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Sulfonamides; Amides; Sulfones; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Xanthines; Purinones; Purines; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines

Study Officials

• Jürgen Brockmöller, Prof.

  Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2013
• First Posted: May 3, 2013
• Study Start: December 1, 2009
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2013
• Last Updated: April 21, 2014

Record last verified: 2014-04

Locations

DE (1)