A Clinical Study to Investigate the Effect of Gemfibrozil or Rifampicin on Blood Concentrations of Selexipag in Healthy Subjects

Study Overview
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Brief Summary
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The primary objectives of this 2-part drug interaction study are as follows: To evaluate the effect of gemfibrozil on the pharmacokinetics (i.e., amount in the blood) of selexipag and its metabolite ACT-333679 (Part I). To evaluate the effect of rifampicin on the pharmacokinetics of selexipag and its metabolite ACT-333679 (Part II).

Detailed Description
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Because non-clinical studies have shown that selexipag and its active metabolite, ACT-333679, are substrates for cytochrome P450 2C8 (CYP2C8), the present clinical study aims at investigating the effect of a strong inhibitor (gemfibrozil) and a moderate inducer (rifampicin) of CYP2C8 on the pharmacokinetic of selexipag and ACT-333679 as recommended by the FDA's Guidance for Industry Drug Interaction Studies (FDA, 2012).

Official Title
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A Single-center, Open-label, Randomized, Two-part, Two-treatment, Two-period Crossover Study to Investigate the Effect of Gemfibrozil or Rifampicin on the Pharmacokinetics of Selexipag and Its Metabolite ACT-333679 in Healthy Male Subjects.

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Selexipag
* Drug: Gemfibrozil
* Drug: Rifampicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent form. Male subjects aged between 18 and 55 years (inclusive) at screening. Body mass index of 18.0 to 28.0 kg/m2 (inclusive) at screening. Healthy on the basis of physical examination, cardiovascular assessments and laboratory tests at screening. Exclusion Criteria: Any contraindication to gemfibrozil or rifampicin treatment. History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might put the subject at risk of participation in the study or 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 full participation in the study or compliance with the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Part 1, sequence AB<br>Subjects participate in two study periods: During the first period (Treatment A), they receive oral selexipag on Day 1. During the second period (Treatment B), they receive multiple oral dose of gemfibrozil from Day 1 to Day 9. Subjects also receive a single oral dose of selexipag on Day 4 concomitantly with gemfibrozil. There is a washout period of 14 to 21 days between the two periods. | Drug: Selexipag<br>* Two selexipag film-coated tablets of 200 µg as single oral dose (total dose = 400 µg)<br>* Other names: ACT-293987;Drug: Gemfibrozil<br>* Gemfibrozil film-coated tablet of 600 mg administered orally b.i.d. from Day 1 to Day 9<br>|
| Experimental: Part 1, sequence BA<br>Subjects participate in two study periods: During the first period (Treatment B), they receive multiple oral dose of gemfibrozil from Day 1 to Day 9. They also receive a single oral dose of selexipag on Day 4 concomitantly with gemfibrozil. During the second period (Treatment A) they receive oral selexipag on Day 1. There is a washout period of 14 to 21 days between the two periods. | Drug: Selexipag<br>* Two selexipag film-coated tablets of 200 µg as single oral dose (total dose = 400 µg)<br>* Other names: ACT-293987;Drug: Gemfibrozil<br>* Gemfibrozil film-coated tablet of 600 mg administered orally b.i.d. from Day 1 to Day 9<br>|
| Experimental: Part 2, sequence AB<br>Subjects participate in two study periods: During the first period (Treatment A), they receive oral selexipag on Day 1. During the second period (Treatment B), they receive rifampicin once daily from Day 1 to Day 9. Subjects also receive a single oral dose of selexipag on Day 7 together with the dose of rifampicin.There is a washout period of 14 to 21 days between the two periods. | Drug: Selexipag<br>* Two selexipag film-coated tablets of 200 µg as single oral dose (total dose = 400 µg)<br>* Other names: ACT-293987;Drug: Rifampicin<br>* Rifampicin film-coated tablet of 600 mg administered orally o.d.from Day 1 to Day 9<br>|
| Experimental: Part 2, sequence BA<br>Subjects participate in two study periods: During the first period (Treatment B), they receive rifampicin once daily from Day 1 to Day 9. Subjects also receive a single oral dose of selexipag on Day 7 together with the dose of rifampicin. During the second period (Treatment A), they receive oral selexipag on Day 1. There is a washout period of 14 to 21 days between the two periods. | Drug: Selexipag<br>* Two selexipag film-coated tablets of 200 µg as single oral dose (total dose = 400 µg)<br>* Other names: ACT-293987;Drug: Rifampicin<br>* Rifampicin film-coated tablet of 600 mg administered orally o.d.from Day 1 to Day 9<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from zero to infinity [AUC(0-inf)] of selexipag and ACT-333679 | AUC(0-inf) is calculated for selexipag and its metabolite, ACT-333679, following administration of selexipag alone or concomitantly with gemfibrozil (Part I) or rifampicin (Part II) | Blood samples at different time points from pre-dose up to 72 hours after selexipag administration in each study period (except for the period with co-administration of gemfibrozil: up to 144 hours) | 
| Maximum plasma concentration (Cmax) of selexipag and ACT-333679 | Cmax is directly derived from the individual plasma concentration-time curves for selexipag and its metabolite, ACT-333679, following administration of selexipag alone or concomitantly with gemfibrozil (Part I) or rifampicin (Part II) | Blood samples at different time points from pre-dose up to 72 hours after selexipag administration in each study period (except for the period with co-administration of gemfibrozil: up to 144 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification [(AUC(0-t)] of selexipag and ACT-333679 | AUC(0-t) is calculated for selexipag and ACT-333679,following administration of selexipag alone or concomitantly with gemfibrozil (Part I) or rifampicin (Part II) | Blood samples at different time points from pre-dose up to 72 hours after selexipag administration in each study period (except for the period with co-administration of gemfibrozil: up to 144 hours) | 
| Time to reach maximum plasma concentration (tmax) of selexipag and ACT-333679 | tmax is directly derived from the individual plasma concentration-time curves for selexipag and its metabolite, ACT-333679, following administration of selexipag alone or concomitantly with gemfibrozil (Part I) or rifampicin (Part II) | Blood samples at different time points from pre-dose up to 72 hours after selexipag administration in each study period (except for the period with co-administration of gemfibrozil: up to 144 hours) | 
| Terminal elimination half-life (t1/2) of selexipag and ACT-333679 | t1/2 is the period of time required for the concentration levels of selexipag or ACT-333679 to be reduced by one-half, following administration of selexipag alone or concomitantly with gemfibrozil (Part I) or rifampicin (Part II) | Blood samples at different time points from pre-dose up to 72 hours after selexipag administration in each study period (except for the period with co-administration of gemfibrozil: up to 144 hours) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics