Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects

• Sponsor: University Hospital, Basel, Switzerland (Other)
• Overall Status: Completed
• CT.gov ID: NCT03990129
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 1.9
• Patients Per Site Per Month: 6.4

Study Details

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 Blood samples were withdrawn over 24 hours and the AUC ratios between metabolite and parent were calculated to determine the phenotype.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 Probands were still exposed to metamizole to ensure potential inhibition. 24 hours plasma samples were withdrawn, area under the curve (AUC) ratios were calculated and compared to the basal state.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

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Two phase study, before-after comparisonTwo 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: Sep 4, 2018
• Actual Primary Completion Date: Oct 31, 2018
• Actual Study Completion Date: Oct 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: 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 [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 [24 hours]

   Maximal Concentration in plasma of parent and metabolite

3. tmax [24 hours]

   time to reach Cmax

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

	Site	City	State	Country	Postal Code
1	Clinical Trial Unit, University Hospital Basel	Basel	BS	Switzerland	4053

Sponsors and Collaborators

• University Hospital, Basel, Switzerland

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University Hospital, Basel, Switzerland
• ClinicalTrials.gov Identifier: NCT03990129
• Other Study ID Numbers: 2018-00753
• First Posted: Jun 18, 2019
• Last Update Posted: Jun 20, 2019
• Last Verified: Jun 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Keywords provided by University Hospital, Basel, Switzerland: Metamizole; Dipyrone; Basel Cocktail; Drug-Drug Interaction; Phenotyping
• Additional relevant MeSH terms: Dipyrone

Study Results

No Results Posted as of Jun 20, 2019