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出境医 / 临床实验 / Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects

Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects

Study Description
Brief Summary:

Investigators conducted a single center, two-phased, open, controlled pharmacokinetic study to investigate the drug-drug interaction potential of metamizole. For this reason, healthy male volunteers were screened.

Enrolled participants were phenotyped on day 1 using the Basel Cocktail (phenotyping cocktail containing specific substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4). After, they received metamizole treatment for 8 days (3 grams per day). On the 8th day (day 9), they were phenotyped again with the Basel Cocktail and the respective phenotypes (d1 vs. d9) were compared.


Condition or disease Intervention/treatment Phase
Inhibition Induction Drug-Drug Interaction Drug: Metamizole Phase 1

Detailed Description:

12 healthy male subjects meeting the inclusion and exclusion criteria were enrolled. On day 1, they ingested a capsule containing the Basel Cocktail (1A2: caffeine, 2B6: efavirenz, 2C9: flurbiprofen, 2C19: omeprazole, 2D6: metoprolol, 3A4: midazolam) in fastened state. Blood samples were withdrawn over 24 hours and the AUC ratios between metabolite and parent were calculated to determine the phenotype.

Probands began metamizole treatment (3000 mg/day) at the day of the 24h measurement. After 3-4 day, probands were returning to the facility to ensure safety during the metamizole treatment, blood cell count and metamizole metabolites were measured. After the 7 days of treatment, probands were exposed again to the Basel Cocktail in a fastened state. Probands were still exposed to metamizole to ensure potential inhibition. 24 hours plasma samples were withdrawn, area under the curve (AUC) ratios were calculated and compared to the basal state. After an end of study visit on the day of the 24h blood sample (following the second study day), probands were discharged.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Two phase study, before-after comparison
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Single-center, Open, Controlled Study to Investigate the Interaction of Metamizole With the Cytochrome p450 System in Healthy Subjects by Application of the Basel Cocktail
Actual Study Start Date : September 4, 2018
Actual Primary Completion Date : October 31, 2018
Actual Study Completion Date : October 31, 2018
Arms and Interventions
Arm Intervention/treatment
Study population
All participants
 Drug: Metamizole
One week treatment with metamizole (500 mg tablets, 2-2-2)
Outcome Measures
Primary Outcome Measures :
  1. Effect on AUC ratio between parent and metabolite [ Time Frame: 12 hours ]
    AUC ratio between parent and metabolite of specific cytochrome P450 substrates to determine a shift which may indicate either induction or inhibition of the specific cytochrome P450

  2. Cmax [ Time Frame: 24 hours ]
    Maximal Concentration in plasma of parent and metabolite

  3. tmax [ Time Frame: 24 hours ]
    time to reach Cmax


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy subjects aged between 18 and 45 years (inclusive) at screening
  • BMI between 18 and 28 kg/m2 (inclusive) and bodyweight at least 50 kg at screening
  • systolic blood pressure: 100-140 mmHg, diastolic blood pressure: 60-90 mmHg and heart rate: 45-90 bpm (inclusive), measured on the leading arm, in the supine position at screening
  • No clinically significant findings on the physical examination at screening
  • Signed informed consent prior to any study-mandated procedure
  • Hematology and clinical chemistry results not deviating from the normal range to clinically relevant extent at screening
  • Ability to communicate well with the investigator to understand and comply with the requirements of the study

Exclusion Criteria:

  • Smoking >5 cigarettes per day
  • History or clinical evidence of alcoholism or drug abuse within the 3- year period prior to screening
  • Loss of ≥250 ml of blood within 3 months prior to screening. Treatment with an investigational drug within 30 days prior to screening
  • Previous systemic treatment with any prescribed or over the counter medication (including herbal medicines such as St John's Wort) within 2 weeks prior to the intended start of the study
  • Inability to stop consumption inducing food products (e.g. grapefruit juice) 72 h before start of the study
  • Excessive caffeine consumption (>8 cups of coffee/ 8l coca cola per day)
  • Legal incapacity or limited legal capacity at screening
  • Positive results from urine drug screen at screening
  • History or clinical evidence of any disease (e.g. gastrointestinal disease: Morbus Crohn, Colitis Ulcerosa, anamnestic gastrointestinal bleeding) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity
  • Known hypersensitivity to Metamizole (Novalgin®) or excipients of the drug formulation
  • Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
Contacts and Locations

Locations
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Switzerland
Clinical Trial Unit, University Hospital Basel
Basel, BS, Switzerland, 4053
Sponsors and Collaborators
University Hospital, Basel, Switzerland
Investigators
Layout table for investigator information
Principal Investigator: Stephan Krähenbühl, Prof. Dr. MD Head of Clinical Pharmacology, University Hospital Basel
Tracking Information
First Submitted Date  ICMJE June 14, 2019
First Posted Date  ICMJE June 18, 2019
Last Update Posted Date June 20, 2019
Actual Study Start Date  ICMJE September 4, 2018
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • Effect on AUC ratio between parent and metabolite [ Time Frame: 12 hours ]
    AUC ratio between parent and metabolite of specific cytochrome P450 substrates to determine a shift which may indicate either induction or inhibition of the specific cytochrome P450
  • Cmax [ Time Frame: 24 hours ]
    Maximal Concentration in plasma of parent and metabolite
  • tmax [ Time Frame: 24 hours ]
    time to reach Cmax
Original Primary Outcome Measures  ICMJE
 (submitted: June 14, 2019)
  • Phenotype [ Time Frame: 12 hours ]
    AUC ratio between parent and metabolite of specific cytochrome P450 substrates
  • Cmax [ Time Frame: 24 hours ]
    Maximal Concentration in plasma of parent and metabolite
  • tmax [ Time Frame: 24 hours ]
    time to reach Cmax
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects
Official Title  ICMJE Single-center, Open, Controlled Study to Investigate the Interaction of Metamizole With the Cytochrome p450 System in Healthy Subjects by Application of the Basel Cocktail
Brief Summary

Investigators conducted a single center, two-phased, open, controlled pharmacokinetic study to investigate the drug-drug interaction potential of metamizole. For this reason, healthy male volunteers were screened.

Enrolled participants were phenotyped on day 1 using the Basel Cocktail (phenotyping cocktail containing specific substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4). After, they received metamizole treatment for 8 days (3 grams per day). On the 8th day (day 9), they were phenotyped again with the Basel Cocktail and the respective phenotypes (d1 vs. d9) were compared.
Detailed Description

12 healthy male subjects meeting the inclusion and exclusion criteria were enrolled. On day 1, they ingested a capsule containing the Basel Cocktail (1A2: caffeine, 2B6: efavirenz, 2C9: flurbiprofen, 2C19: omeprazole, 2D6: metoprolol, 3A4: midazolam) in fastened state. Blood samples were withdrawn over 24 hours and the AUC ratios between metabolite and parent were calculated to determine the phenotype.

Probands began metamizole treatment (3000 mg/day) at the day of the 24h measurement. After 3-4 day, probands were returning to the facility to ensure safety during the metamizole treatment, blood cell count and metamizole metabolites were measured. After the 7 days of treatment, probands were exposed again to the Basel Cocktail in a fastened state. Probands were still exposed to metamizole to ensure potential inhibition. 24 hours plasma samples were withdrawn, area under the curve (AUC) ratios were calculated and compared to the basal state. After an end of study visit on the day of the 24h blood sample (following the second study day), probands were discharged.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Two phase study, before-after comparison
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Inhibition
  • Induction
  • Drug-Drug Interaction
Intervention  ICMJE Drug: Metamizole
One week treatment with metamizole (500 mg tablets, 2-2-2)
Study Arms  ICMJE Study population
All participants
Intervention: Drug: Metamizole
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 14, 2019) 		12
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 31, 2018
Actual Primary Completion Date October 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Healthy subjects aged between 18 and 45 years (inclusive) at screening
  • BMI between 18 and 28 kg/m2 (inclusive) and bodyweight at least 50 kg at screening
  • systolic blood pressure: 100-140 mmHg, diastolic blood pressure: 60-90 mmHg and heart rate: 45-90 bpm (inclusive), measured on the leading arm, in the supine position at screening
  • No clinically significant findings on the physical examination at screening
  • Signed informed consent prior to any study-mandated procedure
  • Hematology and clinical chemistry results not deviating from the normal range to clinically relevant extent at screening
  • Ability to communicate well with the investigator to understand and comply with the requirements of the study

Exclusion Criteria:

  • Smoking >5 cigarettes per day
  • History or clinical evidence of alcoholism or drug abuse within the 3- year period prior to screening
  • Loss of ≥250 ml of blood within 3 months prior to screening. Treatment with an investigational drug within 30 days prior to screening
  • Previous systemic treatment with any prescribed or over the counter medication (including herbal medicines such as St John's Wort) within 2 weeks prior to the intended start of the study
  • Inability to stop consumption inducing food products (e.g. grapefruit juice) 72 h before start of the study
  • Excessive caffeine consumption (>8 cups of coffee/ 8l coca cola per day)
  • Legal incapacity or limited legal capacity at screening
  • Positive results from urine drug screen at screening
  • History or clinical evidence of any disease (e.g. gastrointestinal disease: Morbus Crohn, Colitis Ulcerosa, anamnestic gastrointestinal bleeding) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity
  • Known hypersensitivity to Metamizole (Novalgin®) or excipients of the drug formulation
  • Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03990129
Other Study ID Numbers  ICMJE 2018-00753
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University Hospital, Basel, Switzerland
Study Sponsor  ICMJE University Hospital, Basel, Switzerland
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Stephan Krähenbühl, Prof. Dr. MD Head of Clinical Pharmacology, University Hospital Basel
PRS Account University Hospital, Basel, Switzerland
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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