Clinical trial NCT01845194: Repeated Dose Study for the Investigation of Heritability of and Genetic Influences on Drug Pharmacokinetics
Official title: Open Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics (TWINS II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Drug Biotransformation
Membrane Transport
Keywords: pharmacokinetic
heritability
drug membrane transport
drug biotransformation
Lead sponsor: Institut fuer anwendungsorientierte Forschung und klinische Studien GmbH
Sponsor class: OTHER
First posted: 2013-05-03
Enrollment: 117
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: plasma drug concentrations
timeFrame: up to 24 h after drug application
Secondary outcomes:
measure: PK and metabolic ratios
timeFrame: up to 24 h after drug application
measure: variants in known genetic traits
timeFrame: up to 24 h after drug application
measure: design applicability
timeFrame: 54 months after study start
Other outcomes:
Locations:
city: Goettingen
country: Germany
facility: Dept. of Clinical Pharmacology, Georg-August-University of Goettingen
Study officials:
affiliation: Dept. of Clinical Pharmacology, Georg-August-University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany
name: Jürgen Brockmöller, Prof.
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.