Potential Pharmacokinetic Interaction Between Selexipag and Midazolam in Healthy Male Subjects

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the effect of repeated doses of selexipag on the pharmacokinetics of a single oral dose of midazolam (i.e., how long and how much midazolam is present in the blood)

Detailed Description
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In order to exclude an inductive effect of selexipag in the gastrointestinal tract, this study aims at investigating the effect of selexipag on the PK of midazolam, a sensitive substrate of both hepatic and intestinal cytochrome P450 3A4 (CYP3A4).

Official Title
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A Single-center, Open-label, Randomized, Two-treatment Crossover Study to Investigate the Effect of Selexipag on the Pharmacokinetics of Midazolam and Its Metabolite 1-hydroxymidazolam in Healthy Male Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Midazolam
* Drug: Selexipag


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent form Age from 18 to 45 years (inclusive) at screening Body mass index (BMI) from 18.0 to 28.0 kg/m2 (inclusive) at screening Healthy on the basis of physical examination, cardiovascular assessments and laboratory tests Key Exclusion Criteria: Any contraindication to the study treatments History or clinical evidence of any disease or medical / surgical condition or treatment, which may put the subject at risk of participation in the study or may interfere with the absorption, distribution, metabolism or excretion of the study treatments Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence AB<br>Subjects participate in two study periods: During the first period, they receive a single oral dose of midazolam on Day 1. During the second period, they receive oral selexipag alone from Day 1 to Day 11 and selexipag + midazolam on Day 12. There is a washout period of 14 to 21 days between the two periods. | Drug: Midazolam<br>* Single oral dose of 7.5 mg midazolam (tablet)<br>Drug: Selexipag<br>* Oral administration of selexipag (200 µg film-coated tablet) for 12 consecutive days (with a titration scheme from 400 to 1600 μg b.i.d. )<br>* Other names: ACT-293987;|
| Experimental: Sequence BA<br>Subjects participate in two study periods: During the first period, they receive oral selexipag alone from Day 1 to Day 11 and selexipag + midazolam on Day 12. During the second period, they receive a single oral dose of midazolam on Day 1. There is a washout period of 14 to 21 days between the two periods. | Drug: Midazolam<br>* Single oral dose of 7.5 mg midazolam (tablet)<br>Drug: Selexipag<br>* Oral administration of selexipag (200 µg film-coated tablet) for 12 consecutive days (with a titration scheme from 400 to 1600 μg b.i.d. )<br>* Other names: ACT-293987;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of midazolam following administration of midazolam alone and in combination with selexipag | Cmax is the maximum observed plasma concentration and is directly derived from the individual plasma concentration time curves of midazolam | From pre-dose up to 24 hours after midazolam admisnitration for each treatment period | 
| AUC(0-inf) of midazolam following administration of midazolam alone and in combination with selexipag | AUC(0-inf) is the area under the plasma concentration-time curves of midazolam, calculated from time 0 (pre-dose) to the extrapolated infinite time | From pre-dose up to 24 hours after midazolam admisnitration for each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax of 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag |  | From pre-dose up to 24 hours after midazolam admisnitration | 
| AUC(0-inf) of 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag |  | From pre-dose up to 24 hours after midazolam admisnitration | 
| tmax of midazolam and 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag | tmax is the time to reach Cmax of midazolam and its metabolite (1-hydroxymidazolam), respectively | From pre-dose up to 24 hours after midazolam admisnitration | 
| t½ of midazolam and 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag. | t½ is the terminla half-life of midazolam and its metabolite (1-hydroxymidazolam), and corresponds to the period of time required for the concentration levels of midazolam and its metabolite to be reduced by one-half, respectively | From pre-dose up to 24 hours after midazolam admisnitration | 
| Trough concentration of selexipag and its metabolite ACT-333679 at steady-state | Trough concentrations are measured before morning administration of selexipag | Days 1, 4, 7, 10,12 and 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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selexipag, pharmacokinetics, midazolam