Clinical Study to Investigate Effect of Macitentan on Riociguat Pharmacokinetics

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Riociguat (Adempas); Drug: Macitentan (Opsumit)

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, 68167
    • CRS Clinical Research Services Mannheim

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment A-B; 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); Riociguat film-coated tablets for oral administration at a strength of 1 mg; Drug: Macitentan (Opsumit); Macitentan film-coated tablets for oral administration at a strength of 10 mg; Other Names: ACT-064992

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Actelion

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 9, 2018
• Primary Completion (ACTUAL): February 6, 2018
• Study Completion (ACTUAL): February 6, 2018

Study Registration Dates

• First Submitted: December 27, 2017
• First Submitted That Met QC Criteria: December 27, 2017
• First Posted (ACTUAL): January 3, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2018
• Last Update Submitted That Met QC Criteria: February 7, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: pharmacokinetics; macitentan; riociguat
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Endothelin Receptor Antagonists; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Macitentan; Riociguat
• Other Study ID Numbers: AC-055-123; 2017-003502-41 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No