Inhibition Metamizole 2020

Study Overview
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Brief Summary
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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
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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.

Official Title
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Interaction of Cytochrome P450 Inhibition With Metamizole Metabolism in Healthy Subjects

Conditions
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Drug-drug Interaction

Intervention / Treatment
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* Drug: Novalgin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized cross-over treatment with 3 different sequences
Masking: Single


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metamizole, Inhibition, Cytochrome P450