A Study to Examine the Effect of Daridorexant on the Way the Body Absorbs, Distributes, and Gets Rid of Midazolam and Warfarin in Healthy Male Subjects

NCT05480488 | Completed Phase 1 FDA Drug

• 1 other identifier: ID-078-126
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

A study to examine the effect of daridorexant on the way the body absorbs, distributes, and gets rid of midazolam and warfarin in healthy male subjects

Conditions

Healthy

Outcome Measures

Primary Outcomes (8)

• Maximum concentration (Cmax) of midazolam and its metabolite 1-OH midazolam

  Blood samples for pharmacokinetic analyses of midazolam will be taken at various time points from Day 1 to 2 of Treatment Period A, from Day 1 to 2 of Treatment Period B, and from Day 1 to 2 of Treatment Period C (total duration: 6 days).

• Cmax of S-warfarin

  Blood samples for pharmacokinetic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days).

• Time to reach Cmax (tmax) of midazolam and 1-OH midazolam

  Blood samples for pharmacokinetic analyses of midazolam will be taken at various time points from Day 1 to 2 of Treatment Period A, from Day 1 to 2 of Treatment Period B, and from Day 1 to 2 of Treatment Period C (total duration: 6 days).

• Tmax of S-warfarin

  Blood samples for pharmacokinetic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days).

• Area under the concentration-time curve (AUC) from zero to infinity (AUC0-∞) of midazolam and 1-OH midazolam

  Blood samples for pharmacokinetic analyses of midazolam will be taken at various time points from Day 1 to 2 of Treatment Period A, from Day 1 to 2 of Treatment Period B, and from Day 1 to 2 of Treatment Period C (total duration: 6 days)

• AUC0-∞ of S-warfarin

  Blood samples for pharmacokinetic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days).

• Terminal elimination half-life (t½) of midazolam and 1-OH midazolam

  Blood samples for pharmacokinetic analyses of midazolam will be taken at various time points from Day 1 to 2 of Treatment Period A, from Day 1 to 2 of Treatment Period B, and from Day 1 to 2 of Treatment Period C (total duration: 6 days).

• T½ of S-warfarin

  Blood samples for pharmacokinetic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days).

Secondary Outcomes (6)

• AUC0-144 for international normalized ratio (AUC INR)

  Blood samples for pharmacodynamic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days)

• The maximum effect on INR (INRmax)

  Blood samples for pharmacodynamic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days)

• Time to reach maximum effect of INR (t Emax)

  Blood samples for pharmacodynamic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days)

• AUC0-144 for Factor VII (AUC VII)

  Blood samples for pharmacodynamic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days)

• The maximum effect on Factor VII (VIImax)

  Blood samples for pharmacodynamic analyses of S-warfarin will be taken at various time points from Day 1 to 7 of Treatment Period A and from Day 1 to 7 of Treatment Period B (total duration: 14 days)

Study Arms (1)

• A (midazolam & warfarin), B (daridorexant, midazolam, & warfarin), & C (daridorexant & midazolam)

OTHER

* Treatment A - midazolam and warfarin: In the morning of Day 1, subjects will receive a single oral dose of 2 mg midazolam concomitantly with a single oral dose of 25 mg warfarin under fasted conditions. * Treatment B - daridorexant, midazolam, and warfarin: Subjects will receive an o.d. oral dose of 50 mg daridorexant in the morning from Day 1 to Day 7 under fasted conditions. In addition, in the morning of Day 1, the oral administration of 50 mg daridorexant will be followed 1 h later by a single oral dose of 2 mg midazolam concomitantly with a single oral dose of 25 mg warfarin under fasted conditions. * Treatment C - daridorexant and midazolam: In the morning of Day 1, subjects will receive a single oral dose of 50 mg daridorexant followed 1 h later by a single oral dose of 2 mg midazolam under fasted conditions.

Drug: Midazolam; Drug: Warfarin; Drug: Daridorexant

Interventions

Midazolam DRUG

Subjects will receive a single oral dose of 2 mg midazolam (Treatment A, B, and C).

• A (midazolam & warfarin), B (daridorexant, midazolam, & warfarin), & C (daridorexant & midazolam)

Warfarin DRUG

Subjects will receive a single oral dose of 25 mg warfarin (Treatment A and B).

• A (midazolam & warfarin), B (daridorexant, midazolam, & warfarin), & C (daridorexant & midazolam)

Daridorexant DRUG

Subjects will receive an o.d. oral dose of 50 mg daridorexant from Day 1 to Day 7 of Treatment B and a single oral dose of 50 mg daridorexant on Day 1 of Treatment C.

• A (midazolam & warfarin), B (daridorexant, midazolam, & warfarin), & C (daridorexant & midazolam)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Signed informed consent in a language understandable to the subject prior to any study-mandated procedure.
• Healthy male subject aged between 18 and 45 years (inclusive) at Screening.

You may not qualify if:

• Known hypersensitivity to daridorexant, midazolam, warfarin, or treatments of the same class, or any of their excipients.
• Any history of hemorrhagic disease, whether or not hereditary.
• Any history of complications with bleeding after surgery or tooth extractions and/or frequent nasal, hemorrhoidal, or gingival bleeding.
• Activated partial thromboplastin time (aPTT) \> 40 sec and/or international normalized ratio (INR) \> 1.15 at Screening.
• Platelet count \< 150 or \>400 x 10\^9/L at Screening.
• Clinically relevant findings on the physical examination at Screening.
• Clinically relevant abnormalities on 12-lead ECG, measured after 5 min in the supine position at Screening.
• Clinically relevant findings in clinical laboratory tests (hematology, coagulation, clinical chemistry) at Screening.

Sponsors & Collaborators

• Idorsia Pharmaceuticals Ltd.: lead

Study Sites (1)

Nuvisan GmbH

Neu-Ulm, 89231, Germany

Location

Related Publications (1)

• Zenklusen I, Dingemanse J, Reh C, Gehin M, Kaufmann P. Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects. Drugs R D. 2024 Mar;24(1):97-108. doi: 10.1007/s40268-024-00456-8. Epub 2024 Mar 13.

  PMID: 38472696 DERIVED

MeSH Terms

Interventions

Midazolam; Warfarin; daridorexant

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring

Study Officials

• Clinical Trials

  Idosia Pharmaceuticals Ltd

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a prospective, open-label, fixed-sequence Phase 1 study.

Study Record Dates

• First Submitted: July 27, 2022
• First Posted: July 29, 2022
• Study Start: August 23, 2022
• Primary Completion: September 23, 2022
• Study Completion: October 6, 2022
• Last Updated: November 8, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)