Evaluation of the perpetrator characteristics of metamizole (dipyrone) on the activity of CYP3A4 in healthy volunteers by using a new orodispersible film formulation of midazolam

Phase 1

• Conditions: new ways of drug administrationDrug drug interaction

• Registration Number: DRKS00024795
• Lead Sponsor: Ruprecht-Karls-University Heidelberg, Medical Faculty

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-03-15
• Study Completion: 2021-12-19
• Results First Posted: 2022-10-18
• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: Complete
• Sex: All
• Target Recruitment: 24

Inclusion Criteria

1. Age 18-50 years (y) inclusive at the time of consent,
2. Men, or women of child-bearing potential who are willing to use contraception as detailed in section 7.4, or women not of child-bearing potential (WNCBP), or individuals who are convincingly sexually abstinent,
3. Understanding, ability, and willingness to fully comply with trial interventions and restrictions,
4. Ability to provide written, personally signed and dated informed consent to participate in the trial, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6, and applicable regulations, prior to any trial-related interventions, and
5. No SARS-CoV2- (Serve acute respiratory syndrome coronavirus type 2) vaccination offer at start of trial and no expected SARS-CoV2-vaccination during the treatment period. A prior SARS-CoV2 vaccination has occurred > 2 weeks prior to Visit 1.

Exclusion Criteria

At the time of SCR:
1. Clinically significant or relevant abnormalities in the medical history, physical examination, and laboratory evaluation as assessed by the investigator,
2. Any medical disorder that may require treatment or make the participant unlikely to fully complete the trial, or any condition that presents undue risk from the IMP or trial interventions,
3. Clinically relevant ongoing or clinically relevant history of physical or psychiatric illness as judged by the investigator,
4. Pregnancy or breast feeding,
5. Any acute or chronic illness or clinically relevant finding known or expected to modify absorption, distribution, metabolism, or excretion of midazolam and metamizole,
6. Any known history of severe allergic or anaphylactic reactions to drugs or food or any other clinically significant allergies,
7. Any known allergies to the compound midazolam or additives of midazolam, or known allergies to other benzodiazepines,
8. Clinically relevant findings in any of the following investigations at SCR. Minor deviations of laboratory values from the normal range can be acceptable, if judged by the investigator to be of no clinical relevance for this trial.
a) Hemoglobin (Hb) < 12 g/dl (males) or < 11 g/dl (females),
b) Creatinine (Crea) clearance (Cl) < 60 ml/min (Cockcroft-Gault),
c) Bilirubin > 1.2 x upper limit of normal (ULN), in case of suspected
Gilbert’s disease: non-fasting total bilirubin = 1.2 x ULN and fasting total bilirubin = 1.5 x ULN are acceptable.
d) Alanine aminotransferase (ALT) > 1.1 x ULN,
e) Aspartate aminotransferase (AST) > 1.2 x ULN,
f) Creatine kinase (CK) not within normal limits (volunteers with CK elevations between 1-3 x ULN may be included if troponin T is negative), and
9. A positive result in the drug screening test at SCR,
10. Use of any medication (prescription medication, non-prescription medication including multivitamin or herbal preparations) with active ingredients, or any intake of substances known to induce or inhibit CYP3A4 or drug transporters within a period of less than 5 times the respective elimination half-life (t1/2) with regard to the expected date of the first dose of IMP, this does not apply to hormonal contraception, iodine and thyroid hormones,
11. Any consumption of grapefruit within 7 d prior to the expected date of first dose of IMP and expected noncompliance to refrain from grapefruit intake until the last visit of this trial. Minor intake of grapefruit may be accepted, if judged by the investigator to have no impact on metabolism,
12. Pathologic alcohol consumption, and
13. Use of an IMP within 30 d prior to the expected date of receiving the first dose of IMP or active enrolment in another drug or vaccine clinical trial.

Specific exclusion criteria for Part II, not applicable for part I
14. Blood cell count in the following ranges,
a. hemoglobin (Hb) < 12 g/dl (males) or < 11 g/dl (females),
b. white blood cell count and neutrophil count outside normal range
c. thrombocyte count outside normal range
15. History of bone marrow suppression (reported episodes of clinically relevant suppression of blood count),
16. History of or current hepatic porphyria,
17. History of analgesic asthma or angioedema,
18. Relevant past or current hepatic or renal dysfunction,
19. Body weight < 53 kg,
20. History of glucose-6-phosphate dehydrogenase deficiency, or
21. Any known allergies to metamizole or additives of the drug.

At visit 1, prior to dos

Study & Design

• Study Type: interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Part I: Geometric mean ratio AUC (0-inf.) and C max of a single dose of midazolam orodispersible film (immediately swallowed) for 30 µg and 3 mg.<br><br>Part II: Geometric mean ratio of AUC (2-4) and C max of µ-midazolam before and under metamizole doses on steady-state

Secondary Outcome Measures

Name	Time	Method
Part I:<br>Geometric mean ratio of AUC0-10 and Cmax of a single dose of midazolam ODF (IS) and midazolam oral solution for 30 µg and 3 mg.<br>• Geometric mean ratio of AUC0-8, AUC0-10 and Cmax of midazolam ODF (minimal oral cavity residence time, IS) and an i.v. dose of midazolam to evaluate absolute bioavailability,<br>• Geometric mean ratio of AUC0-8, AUC0-10 and Cmax of midazolam ODF with 2 different oral cavity residence times (IS and DS) for 2 different doses,<br>• Linearity of AUC0-8 and Cmax related to dose, and<br>• Frequency, severity, seriousness, relatedness, expectedness, and outcome of AE under trial medication.<br><br>Part II:<br>• Changes in PK parameter of µ-dosed midazolam under the influence of metamizole over time, and<br>• Frequency, severity, seriousness, relatedness, expectedness, and outcome of AE under trial medication.<br>• PK and concentrations of metamizole metabolites over time, and<br>• Changes in metabolic products under the influence of metamizole.