Pharmacokinetic Interactions of Metamizole (Dipyrone) in Healthy Subjects

Drug-Drug Interaction Clinical Trial

Official title:

Single-center, Open, Controlled Study to Investigate the Interaction of Metamizole With the Cytochrome p450 System in Healthy Subjects by Application of the Basel Cocktail

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03990129
• Other study ID #: 2018-00753
• Status: Completed
• Phase: Phase 1
• Start date: September 4, 2018
• Est. completion date: October 31, 2018

Study information

• Verified date: June 2019
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Investigators conducted a single center, two-phased, open, controlled pharmacokinetic study to investigate the drug-drug interaction potential of metamizole. For this reason, healthy male volunteers were screened.

Enrolled participants were phenotyped on day 1 using the Basel Cocktail (phenotyping cocktail containing specific substrates for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4). After, they received metamizole treatment for 8 days (3 grams per day). On the 8th day (day 9), they were phenotyped again with the Basel Cocktail and the respective phenotypes (d1 vs. d9) were compared.

Description:

12 healthy male subjects meeting the inclusion and exclusion criteria were enrolled. On day 1, they ingested a capsule containing the Basel Cocktail (1A2: caffeine, 2B6: efavirenz, 2C9: flurbiprofen, 2C19: omeprazole, 2D6: metoprolol, 3A4: midazolam) in fastened state. Blood samples were withdrawn over 24 hours and the AUC ratios between metabolite and parent were calculated to determine the phenotype.

Probands began metamizole treatment (3000 mg/day) at the day of the 24h measurement. After 3-4 day, probands were returning to the facility to ensure safety during the metamizole treatment, blood cell count and metamizole metabolites were measured. After the 7 days of treatment, probands were exposed again to the Basel Cocktail in a fastened state. Probands were still exposed to metamizole to ensure potential inhibition. 24 hours plasma samples were withdrawn, area under the curve (AUC) ratios were calculated and compared to the basal state. After an end of study visit on the day of the 24h blood sample (following the second study day), probands were discharged.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: October 31, 2018
• Est. primary completion date: October 31, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

• Healthy subjects aged between 18 and 45 years (inclusive) at screening

• BMI 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 at screening

• Signed informed consent prior to any study-mandated procedure

• Hematology 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 systemic 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

• Inability to stop consumption inducing food products (e.g. grapefruit juice) 72 h before start of the study

• Excessive caffeine consumption (>8 cups of coffee/ 8l coca cola per day)

• Legal incapacity or limited legal capacity at screening

• Positive results from urine drug screen at screening

• History or clinical evidence of any disease (e.g. gastrointestinal disease: Morbus Crohn, Colitis Ulcerosa, anamnestic gastrointestinal bleeding) and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity

• Known hypersensitivity to Metamizole (Novalgin®) or excipients of the drug formulation

• Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

Related Conditions & MeSH terms

• Drug-Drug Interaction
• Induction
• Inhibition

Intervention

Drug:
• Metamizole
One week treatment with metamizole (500 mg tablets, 2-2-2)

Locations

Country	Name	City	State
Switzerland	Clinical Trial Unit, University Hospital Basel	Basel	BS

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland

Country where clinical trial is conducted

Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect on AUC ratio between parent and metabolite	AUC ratio between parent and metabolite of specific cytochrome P450 substrates to determine a shift which may indicate either induction or inhibition of the specific cytochrome P450	12 hours
Primary	Cmax	Maximal Concentration in plasma of parent and metabolite	24 hours
Primary	tmax	time to reach Cmax	24 hours