Clinical Study to Investigate Effect of Macitentan on Riociguat Pharmacokinetics

Study Overview
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Brief Summary
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Both macitentan and riociguat are indicated in the treatment of pulmonary arterial hypertension (PAH) and may be administered concomitantly. The primary objective of this study is to evaluate the effect of macitentan administered for 11 days on the pharmacokinetics (PK) (i.e., amount and time of presence in the blood of riociguat) of a single dose of riociguat in healthy male subjects.

Official Title
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A Single-center, Open-label, One-sequence, Two-treatment Study to Investigate the Effect of Macitentan at Steady State on the Pharmacokinetics of Riociguat in Healthy Male Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Riociguat (Adempas)
* Drug: Macitentan (Opsumit)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male subjects aged between 18 and 45 years (inclusive) at screening who signed informed consent prior to any study-mandated procedure; Healthy on the basis of physical examination, cardiac evaluations (12-lead ECG) and laboratory tests performed at screening; Body mass index of 18 to 30 Kg/m2 (inclusive) at screening; Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 50-90 beats per minute (inclusive). Key Exclusion Criteria: Known allergic reactions or hypersensitivity to macitentan, riociguat, any drug of the same classes, or any of their excipients; Any contraindication for riociguat treatment; Known hypersensitivity or allergy to natural rubber latex; Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions; History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism, or excretion of the study treatments; Previous treatment with any prescribed medications (including vaccines) or over the counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 3 weeks prior to first study treatment administration; Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol. Other protocol defined inclusion and exclusion criteria may apply.

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: Single Group Assignment
Interventional Model Description: All the subjects included in the study will be included in a single group and will receive the drugs according to the same sequence
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A-B<br>All subjects will receive treatment A followed by treatment B. Treatment A consists of a single oral dose (1 mg) of riociguat (Adempas) on Day 1. Treatment B consists of a loading oral dose of 30 mg macitentan (Opsumit) (3 tablets of 10 mg) on Day 5, then 10 mg of macitentan once daily from Day 6 to Day 15, with a concomitant administration of riociguat (1 mg) on Day 10. | Drug: Riociguat (Adempas)<br>* Riociguat film-coated tablets for oral administration at a strength of 1 mg<br>Drug: Macitentan (Opsumit)<br>* Macitentan film-coated tablets for oral administration at a strength of 10 mg<br>* Other names: ACT-064992;|

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 (AUC) from zero to infinity [AUC(0-inf)] of riociguat | AUC(0-inf) of riociguat will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| Maximum plasma concentration (Cmax) of riociguat | The maximum observed plasma concentration of riociguat will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to reach Cmax (tmax) of riociguat and its metabolite M1 | The maximum observed time to reach Cmax of riociguat and M1 will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| Elimination half life (t1/2) of riociguat and its metabolite M1 | t1/2 of riociguat and M1 will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| AUC(0-t) of riociguat and its metabolite M1 | AUC(0-t) is the area under the plasma concentration-time curve from zero to time t of the last measured concentration above the limit of quantification. It will be determined for both riociguat and its metabolite M1 following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| AUC(0-inf) of riociguat metabolite M1 | AUC(0-inf) of M1 will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| Maximum plasma concentration (Cmax) of riociguat metabolite M1 | The maximum observed plasma concentration of M1 will be assessed following administration of riociguat alone or concomitantly with macitentan. | Day 1 (pre-dose to 96 hours post-dose ), Day 10 (pre-dose to 144 hours post-dose) | 
| Trough concentration (Ctrough) of macitentan and its metabolite ACT-132577 | Ctrough of macitentan and its metabolite ACT-132577 will be assessed during the treatment period with macitentan (Day 10 to Day 15) | Day 10 to Day 15 (before macitentan administration) and in the morning of Day 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, macitentan, riociguat