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Open Label Study for the Functional Characterization of Drug Metabolism and Transport (IKP243)

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ClinicalTrials.gov Identifier: NCT01788254
Recruitment Status : Completed
First Posted : February 11, 2013
Last Update Posted : May 27, 2015
Sponsor:
Information provided by (Responsible Party):
Matthias Schwab, University Hospital Tuebingen

Brief Summary:

Aim of this study is to comprehensively assess in healthy volunteers the metabolic processes and factors that define drug response. Sources of variability are to be investigated and factors that can alter the hepatic metabolism and the pharmacokinetics of drugs shall be quantified.

Determination of variability is important when the pharmacokinetics of new drugs is being investigated and when the concept of individualized medicine is to be further developed. It is important to identify and differentiate between pharmaceutical, physiological (e.g. liver blood flow, renal function), environmental (e.g. foods and lifestyle), and genetic sources of inter-individual variability. For instance, inaccurate or false conclusions may be drawn from a single pharmacokinetic study, if the investigated medicine is metabolized by an enzyme with large inter-individual variability. Knowing the causes of variability and of the quantitative contribution of various processes might help to improve the oral formulations of drugs, might help selecting the right preclinical tests and selection criteria during clinical development, provide the basis to understand the influence of disease and to optimize established drug treatments in order to make future drug treatment safer and more efficient.

This study is designed as an add-on to the study "TWINS: Open Label Repeated Dose Study for the Evaluation of Heritability of and Genetic Influences on Drug Pharmacokinetics" (Eudra-CT: 2008-006223-31). Twins are not a random sample of the population, and they differ in their developmental environment. In this sense they are not representative for the population Thus, the results of TWINS cannot be automatically generalized but instead require validation in a representative population sample. While both studies assess pharmacologic factors important for drug response, TWINS contributes in particular data on the heritability of these processes.


Condition or disease Intervention/treatment Phase
Genotype-related Drug Metabolism Drug: Codeine Drug: Midazolam Drug: pravastatin Drug: Talinolol Drug: torsemide Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 144 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Open Label Study for the Functional Characterization of Drug Metabolism and Transport
Study Start Date : January 2012
Actual Primary Completion Date : May 2015
Actual Study Completion Date : May 2015

Arm Intervention/treatment
Experimental: Drug cocktail
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).
Drug: Codeine
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).

Drug: Midazolam
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).

Drug: pravastatin
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).

Drug: Talinolol
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).

Drug: torsemide
A single oral low dose of codeine 5 mg and midazolam 1 mg administered as drop, pravastatin 5 mg, talinolol 2.5 mg, and torsemide 0.25 mg provided in capsules will be given together at the same time point (cocktail).




Primary Outcome Measures :
  1. Blood levels and clearance (dose/AUC) of midazolam [ Time Frame: 8 hours ]
  2. Blood levels and clearance (dose/AUC) of torsemide [ Time Frame: 8h ]
  3. Blood levels and clearance (dose/AUC) of codeine [ Time Frame: 8h ]
  4. Blood levels and clearance (dose/AUC) of talinolol [ Time Frame: 8h ]
  5. Blood levels and clearance (dose/AUC) of pravastatin [ Time Frame: 8h ]

Secondary Outcome Measures :
  1. determine metabolite profile [ Time Frame: 8 hours ]
    To determine metabolite profile of the phenotyping probes and to assess Pharmacokinetic parameters and/or metabolic ratios in relation to underlying genotypes as well as to validate the heritability estimates derived from TWINS.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
  • Bodyweight not less than 48 kg and not more than 120 kg. BMI not less than 18 kg/m² and not greater than 33 kg/m².
  • Smokers and nonsmokers. Smoking siblings will only be included if both siblings are smoking to a similar extend (+/- 10 cigarettes per day)
  • healthy volunteers
  • 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 of the same gender are considered.

Exclusion Criteria:

  • Participation in a clinical trial involving the administration of medicines 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 thrombocyte donation during the last 30 days prior to application of the test drugs.
  • Pregnancy or lactation period
  • Any relevant clinical and pathological findings at physical examination, ECG, taking blood pressure or in clinical chemistry tests (deviation of more than 10% of the normal range).
  • Positive signal from urinary drug test
  • Raynaud's syndrome
  • 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) an oral contraceptives.
  • History of severe hypersensitivity reactions and anaphylaxis.
  • History of intolerance or allergic reactions to or contraindication for any of the investigational products.
  • Clinically significant diseases as judged by the investigator.
  • Contraindication against MRI.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01788254


Locations
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Germany
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
Stuttgart, Germany, 70376
Abteilung Klinische Pharmakologie
Tübingen, Germany, 72076
Sponsors and Collaborators
Matthias Schwab
Investigators
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Principal Investigator: Matthias Schwab, Prof., M.D. Dr. Margarete Fischer Bosch Institute of Clinical Pharmacology and University of Tuebingen
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Responsible Party: Matthias Schwab, Prof. M.D., University Hospital Tuebingen
ClinicalTrials.gov Identifier: NCT01788254    
Other Study ID Numbers: IKP243
2011-002291-16 ( EudraCT Number )
First Posted: February 11, 2013    Key Record Dates
Last Update Posted: May 27, 2015
Last Verified: May 2015
Keywords provided by Matthias Schwab, University Hospital Tuebingen:
pharmacokinetic/genetic
Cyp450 polymorphisms
Noninvasive functional characterization of liver heart and kidneys using MRI
Additional relevant MeSH terms:
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Talinolol
Torsemide
Midazolam
Codeine
Pravastatin
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors
Analgesics, Opioid
Narcotics
Analgesics
Sensory System Agents
Peripheral Nervous System Agents