Inhibition Metamizole 2020

Sponsor

University Hospital, Basel, Switzerland (Other)

Overall Status

Completed

CT.gov ID

NCT04621253

Collaborator

(none)

Enrollment

Location

Arms

5.1

Actual Duration (Months)

2.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug-drug Interaction	Drug: Novalgin	Phase 1

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 Design

Study Type:

Interventional

Actual Enrollment :

12 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Randomized cross-over treatment with 3 different sequencesRandomized cross-over treatment with 3 different sequences

Masking:

Single (Investigator)

Masking Description:

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.

Primary Purpose:

Treatment

Official Title:

Interaction of Cytochrome P450 Inhibition With Metamizole Metabolism in Healthy Subjects

Actual Study Start Date :

Apr 29, 2020

Actual Primary Completion Date :

Oct 2, 2020

Actual Study Completion Date :

Oct 2, 2020

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Assessment of the area under the plasma concentration vs time (AUC) [Study day (24 hours)]
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
Assessment of peak plasma concentration (Cmax) [Study day (24 hours)]
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
Assessment of the time to reach peak plasma concentration (tmax) [Study day (24 hours)]
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
Assessment of the half-life (t1/2) [Study day (24 hours)]
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

Secondary Outcome Measures

Compliance to the Pretreatment with Ciprofloxacin and Fluconazole [Study day (24 hours)]
Assessment of the area under the plasma concentration vs time of ciprofloxacin and fluconazole on the study day

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital	Basel		Switzerland	4000

Sponsors and Collaborators

University Hospital, Basel, Switzerland

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

University Hospital, Basel, Switzerland

ClinicalTrials.gov Identifier:

NCT04621253

Other Study ID Numbers:

2019-01404

First Posted:

Nov 9, 2020

Last Update Posted:

Nov 9, 2020

Last Verified:

Nov 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Keywords provided by University Hospital, Basel, Switzerland

Metamizole

Inhibition

Cytochrome P450

Additional relevant MeSH terms:

Dipyrone

Study Results

No Results Posted as of Nov 9, 2020