Clinical Study to Investigate the Effect of Macitentan on the Concentrations of Rosuvastatin in the Blood of Healthy Male Subjects

Study Overview
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Brief Summary
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The aim of this Phase 1 trial is to study a potential drug-drug interaction between macitentan and rosuvastatin, a model substrate of various transporter proteins (e.g. in the gut).

Detailed Description
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Rosuvastatin is a substrate of various transporter proteins including breast cancer resistance protein (BCRP) and organic anion-transporting polypeptides (OATP). It is unknown to which extent macitentan has an effect, if any, on BCRP transporters, especially intestinal BCRP. The primary purpose of this Phase 1 study is to investigate the effect of macitentan on the pharmacokinetics of rosuvastatin, a model BCRP substrate.

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 Rosuvastatin in Healthy Male Subjects.

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Rosuvastatin
* Drug: Macitentan


Participation Criteria
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Eligibility Criteria
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Principal Inclusion Criteria: Signed informed consent in the local language prior to any study-mandated procedure. Healthy male subjects aged between 18 and 55 years (inclusive) at screening. No clinically significant findings on the physical examination at screening. Body mass index of 18.0 to 30.0 kg/m2 (inclusive) at screening. Systolic blood pressure 100-140 mmHg, diastolic blood pressure 60-90 mmHg, and pulse rate 50-90 beats per minute (inclusive), measured on the dominant arm, after 5 min in the supine position at screening. 12-lead electrocardiogram (ECG) without clinically relevant abnormalities, measured after 5 min in the supine position at screening. Hematology and clinical chemistry test results not deviating from the normal range to a clinically relevant extent at screening. Negative results from urine drug screen and alcohol breath test at screening and Day -1. Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study. Principal Exclusion Criteria: Known allergic reactions or hypersensitivity to macitentan, rosuvastatin, any drug of the same classes, or any of their excipients. Any contraindication for rosuvastatin treatment. History or clinical evidence of myopathy. Subjects of Asian race. Known hypersensitivity or allergy to natural rubber latex. Values of hepatic aminotransferase (alanine aminotransferase and aspartate aminotransferase) outside of the normal range at screening. Hemoglobin or hematocrit outside of the normal range at screening. 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 treatment(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed). Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions. Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture). Previous exposure to macitentan. Previous exposure to rosuvastatin. Treatment with another investigational drug within 3 months prior to screening or participation in more than 3 investigational drug studies within 1 year prior to screening. History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening. Excessive caffeine consumption, defined as ≥ 800 mg per day at screening. Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum or electronic cigarettes) within 3 months prior to screening and inability to refrain from nicotine intake from screening until End-Of-Study (EOS). 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. Loss of 250 mL or more of blood within 3 months prior to screening. Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening. Positive results from the HIV serology at screening. Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol. Legal incapacity or limited legal capacity at screening.

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

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: All subjects will receive rosuvastatin alone (treatment A) or with macitentan at steady state (treatment B). A fixed sequence design was selected to avoid a lengthy washout period and unnecessary prolongation of subjects' participation in the study.
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 (treatment A), they receive a single oral dose of rosuvastatin on Day 1. During the second period (treatment B), they receive a single oral loading dose of macitentan on Day 5 and oral doses of macitentan from Day 6 to Day 16 (i.e., 11 doses). Subjects receive a single oral dose of 10 mg rosuvastatin concomitantly with macitentan in the morning of Day 10. | Drug: Rosuvastatin<br>* Single oral dose of 10 mg rosuvastatin (film-coated tablet) on Day 1 and Day 10<br>Drug: Macitentan<br>* Single oral dose of 30 mg macitentan (film-coated tablet) on Day 5 and 10 mg macitentan administered orally from Day 6 to Day 16<br>* Other names: ACT-064992;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-inf) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B) | AUC(0-inf) is the area under the plasma concentration-time curves of rosuvastatin, calculated from time zero to the extrapolated infinite time | From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17) | 
| Cmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B) | Cmax is the maximum observed plasma concentration and is directly derived from the individual plasma concentration time curves of rosuvastatin | From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B) | The time to reach maximum plasma concentration (tmax) of rosuvastatin | From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17) | 
| t½ of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B) | t½ is the terminal half-life of rosuvastatin and corresponds to the period of time required for the concentration levels of rosuvastatin to be reduced by one-half | From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17) | 
| AUC(0-t) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B) | AUC(0-t) is the area under the plasma concentration-time curve from time zero to time t of the last measured concentration above the limit of quantification of rosuvastatin | From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17) | 
| Trough plasma concentrations of macitentan and its metabolite ACT-132577 | Trough concentrations of macitentan and ACT-132577 are measured before oral administration of macitentan | From Day5 to Day17 | 
| Change from baseline in supine blood pressure | Change from baseline to each time point of measurement during study period | From Day1 to end-of-study visit (Day 26-28) | 
| Change from baseline in pulse rate | Change from baseline to each time point of measurement during study period | From Day1 to end-of-study visit (Day 26-28) | 
| Change from baseline in heart rate (HR) | Change from baseline to each time point of measurement during study period | From Day1 to end-of-study visit (Day 26-28) | 
| Change from baseline in ECG variables | Change from baseline to each time point of measurement during study period in ECG variables: PR, QRS, QT, RR, and QT corrected for Bazett's and Fridericia's formulae (QTcB and QTcF, respectively) | From Day1 to end-of-study visit (Day 26-28) | 
| Change from baseline to end-of-study (EOS) in body weight | Change in body weight measured in kg during study period | From Day1 to end-of-study visit (Day 26-28) | 
| Change from baseline in clinical laboratory tests | Change from baseline to each time point of measurement during study period for clinical laboratory tests (hematology, clinical chemistry, serology) | From Day1 to end-of-study visit (Day 26-28) | 
| Incidence rate of treatment-emergent treatment-emergent adverse events (AEs) and serious adverse events (SAEs) | Incidence rates of treatment-emergent AEs including abnormalities in ECG variables during each treatment as well as AEs leading to the discontinuation of study treatment. A treatment-emergent AE is any AE temporally associated with the use of a study treatment, whether or not considered related to the study treatment. | From Day1 to follow-up period (Day46-48) | 

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