Inhibition Metamizole 2020

NCT04621253 | Completed Phase 1

• 1 other identifier: 2019-01404
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical phase I trial had 3 arms: inhibition by fluconazole, inhibition by ciprofloxacin and placebo. Subjects were treated for 3 days prior to the study day. The intervention was a single dose of 1 gram metamizole. We took blood samples at set time points and analysed the concentration of the main metabolites of metamizole at each time point in plasma.

Conditions

Drug-drug Interaction

Keywords

Metamizole; Inhibition; Cytochrome P450

Outcome Measures

Primary Outcomes (4)

• Assessment of the area under the plasma concentration vs time (AUC)

  Assessment of the change in AUC of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms

  Study day (24 hours)

• Assessment of peak plasma concentration (Cmax)

  Assessment of the change of Cmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms

  Study day (24 hours)

• Assessment of the time to reach peak plasma concentration (tmax)

  Assessment of the change in tmax of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms

  Study day (24 hours)

• Assessment of the half-life (t1/2)

  Assessment of the change in t1/2 of the main metabolites of metamizole (4-methylaminoantipyrine, 4-aminoantipyrine, 4-acetylaminoantipyrine and 4-formylaminoantipyrine) in the 3 arms

  Study day (24 hours)

Secondary Outcomes (1)

• Compliance to the Pretreatment with Ciprofloxacin and Fluconazole

  Study day (24 hours)

Study Arms (3)

Ciprofloxacin

ACTIVE COMPARATOR

Day 1: 750 mg ciprofloxacin capsule in the morning and evening Day 2: 750 mg ciprofloxacin capsule in the morning and evening Day 3: 750 mg ciprofloxacin capsule in the morning and evening Day 4: Study day, 750 mg ciprofloxacin 1h prior to 1000 mg metamizole.

Drug: Novalgin

Fluconazole

ACTIVE COMPARATOR

Day 1: 400 mg fluconazole in the morning, placebo capsule in the evening Day 2: 200 mg fluconazole in the morning, placebo capsule in the evening Day 3: 200 mg fluconazole in the morning, placebo capsule in the evening Day 4: Study day, 200 mg fluconazole 1h prior to 1000 mg metamizole.

Drug: Novalgin

Placebo

PLACEBO COMPARATOR

Day 1: placebo capsule in the morning and evening Day 2: placebo capsule in the morning and evening Day 3: placebo capsule in the morning and evening Day 4: Study day, placebo capsule 1h prior to 1000 mg metamizole.

Drug: Novalgin

Interventions

Novalgin DRUG

Single dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake

Ciprofloxacin; Fluconazole; Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Body mass index 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 on the physical examination at screening
• Signed informed consent prior to any study-mandated procedure
• Haematology 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

You may not qualify if:

• 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 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
• Legal incapacity or limited legal capacity at screening
• Positive results from urine drug screen at screening
• History or clinical evidence of any disease
• Known hypersensitivity to Metamizole (Novalgin®), ciprofloxacin (Ciproxin®), fluconazole (Diflucan®) or any other excipients in the drug formulation

Sponsors & Collaborators

• University Hospital, Basel, Switzerland: lead

Study Sites (1)

University Hospital

Basel, 4000, Switzerland

Location

Related Publications (2)

• Bachmann F, Duthaler U, Rudin D, Krahenbuhl S, Haschke M. N-demethylation of N-methyl-4-aminoantipyrine, the main metabolite of metamizole. Eur J Pharm Sci. 2018 Jul 30;120:172-180. doi: 10.1016/j.ejps.2018.05.003. Epub 2018 May 8.

  PMID: 29746911 RESULT

• Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet. 1995 Mar;28(3):216-34. doi: 10.2165/00003088-199528030-00004.

  PMID: 7758252 RESULT

MeSH Terms

Conditions

Inhibition, Psychological

Interventions

Dipyrone

Condition Hierarchy (Ancestors)

Behavior

Intervention Hierarchy (Ancestors)

Aminopyrine; Pyrazolones; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Masking Details: Ciprofloxacin, Fluconazole and Placebo Capsules were produced under good manufacturing practice conditions and randomized by the responsible pharmacist. The investigator received emergency envelops in case of severe adverse reactions connected to the pretreatment to unblind the study, however the pharmacist retained the detailed randomization plan.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized cross-over treatment with 3 different sequences

Study Record Dates

• First Submitted: October 26, 2020
• First Posted: November 9, 2020
• Study Start: April 29, 2020
• Primary Completion: October 2, 2020
• Study Completion: October 2, 2020
• Last Updated: November 9, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)