Inhibition Metamizole 2020

NCT ID: NCT04621253

Last Updated: 2020-11-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-29
• Study Completion Date: 2020-10-02

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.

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.

Conditions

Drug-drug Interaction

Keywords

Metamizole; Inhibition; Cytochrome P450

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Novalgin

Intervention Type: DRUG

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

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.

Group Type: ACTIVE_COMPARATOR

Novalgin

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Novalgin

Intervention Type: DRUG

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

Interventions

Novalgin

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

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

University Hospital, Basel, Switzerland

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University Hospital

Basel, , Switzerland

Countries

Switzerland

References

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.

Reference Type: RESULT

PMID: 29746911 (View on PubMed)

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.

Reference Type: RESULT

PMID: 7758252 (View on PubMed)

Other Identifiers

2019-01404

Identifier Type: -

Identifier Source: org_study_id