Inhibition Metamizole 2020

Interaction of Cytochrome P450 Inhibition With Metamizole Metabolism in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Drug-drug Interaction
• Intervention / Treatment: Drug: Novalgin

Detailed Description

While the clinical pharmacokinetics of metamizole have been described in detail before, the enzymes responsible for the metabolism have not been identified yet (except for the acetylation of 4-aminoantipyrine). Former investigations delivered mixed results and the question of the participation of the hepatic cytochrome p450 enzymes could not been answered.

Thus, a double-blind randomized cross over clinical phase I study with healthy, male, caucasian volunteers was conducted. After giving consent for participation and enrolment, the subjects were treated for 3 days with either one inhibitor (either ciprofloxacin, CYP1A2 inhibitor, or fluconazole, strong CYP2C9 and moderate CYP2C19 and CYP3A4 inhibitor) or placebo. The doses were 750 mg ciprofloxacin twice daily for 3 days and in the morning of the study day or 400 mg fluconazole loading dose with consecutive 200 mg fluconazole once daily. For the study day, the subject were invited to the study center and a venous access was placed on the non-dominant arm. The last dose of either inhibitor or placebo was taken 1h prior to a single dose of 1000 mg metamizole. Blood samples were drawn at t: 0h, 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 12h and 24h. The blood samples were centrifuged, the plasma was isolated and frozen at -20°C. All subjects received both inhibitors and placebo treatment, attending to a total of 3 study days. Furthermore, the genotype for CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP2D6 was assessed.

Plasma samples will be analyzed and the concentrations of the main metabolites of metamizole and the inhibitors will be measured. Pharmacokinetic parameters such as maximal concentration, half life, time to reach maximal concentration and the area under the curve will be assessed and compared.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4000
    • University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• 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

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 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ciprofloxacin; 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; Single dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake
Active Comparator: Fluconazole; 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; Single dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake
Placebo Comparator: Placebo; 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; Single dose of 1000 mg metamizole, 1h after the last inhibitor or placebo intake

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compliance to the Pretreatment with Ciprofloxacin and Fluconazole	Assessment of the area under the plasma concentration vs time of ciprofloxacin and fluconazole on the study day	Study day (24 hours)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2020
• Primary Completion (Actual): October 2, 2020
• Study Completion (Actual): October 2, 2020

Study Registration Dates

• First Submitted: October 26, 2020
• First Submitted That Met QC Criteria: November 3, 2020
• First Posted (Actual): November 9, 2020

Study Record Updates

• Last Update Posted (Actual): November 9, 2020
• Last Update Submitted That Met QC Criteria: November 3, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Cytochrome P450; Inhibition; Metamizole
• 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: 2019-01404

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