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

Study Overview
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Brief Summary
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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

Official Title
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A Single-center, Open-label Study to Investigate the Effect of Single- and Multiple-dose Daridorexant on the Pharmacokinetics of Midazolam and Its Metabolite 1-hydroxymidazolam, and the Effect of Single-dose Daridorexant on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Midazolam
* Drug: Warfarin
* Drug: Daridorexant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

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: Other
Intervention Model: Sequential Assignment
Interventional Model Description: This is a prospective, open-label, fixed-sequence Phase 1 study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: • A (midazolam & warfarin), B (daridorexant, midazolam, & warfarin), & C (daridorexant & midazolam)<br>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<br>* Subjects will receive a single oral dose of 2 mg midazolam (Treatment A, B, and C).<br>Drug: Warfarin<br>* Subjects will receive a single oral dose of 25 mg warfarin (Treatment A and B).<br>Drug: Daridorexant<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| Time to reach maximum effect of Factor VII (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) |