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

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.

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).

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.

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.