Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects

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

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.

Study Overview

• Status: Completed
• Conditions: Inhibition; Drug-Drug Interaction; Induction
• Intervention / Treatment: Drug: Metamizole

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 Blood samples were withdrawn over 24 hours and the AUC ratios between metabolite and parent were calculated to determine the phenotype.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 Probands were still exposed to metamizole to ensure potential inhibition. 24 hours plasma samples were withdrawn, area under the curve (AUC) ratios were calculated and compared to the basal state.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: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • BS
    • Basel, BS, Switzerland, 4053
      • Clinical Trial Unit, University Hospital Basel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Study population; All participants	Drug: Metamizole; One week treatment with metamizole (500 mg tablets, 2-2-2)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect on AUC ratio between parent and metabolite	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	12 hours
Cmax	Maximal Concentration in plasma of parent and metabolite	24 hours
tmax	time to reach Cmax	24 hours

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland
• Investigators: Principal Investigator: Stephan Krähenbühl, Prof. Dr. MD, Head of Clinical Pharmacology, University Hospital Basel

Study record dates

Study Major Dates

• Study Start (Actual): September 4, 2018
• Primary Completion (Actual): October 31, 2018
• Study Completion (Actual): October 31, 2018

Study Registration Dates

• First Submitted: June 14, 2019
• First Submitted That Met QC Criteria: June 14, 2019
• First Posted (Actual): June 18, 2019

Study Record Updates

• Last Update Posted (Actual): June 20, 2019
• Last Update Submitted That Met QC Criteria: June 19, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Phenotyping; Drug-Drug Interaction; Dipyrone; Metamizole; Basel Cocktail
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antipyretics; Dipyrone
• Other Study ID Numbers: 2018-00753

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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