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.
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Cmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Other
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 55 Years (Adult)
- Sex
- Male
- Accepts Healthy Volunteers
- Yes
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 -
- •Ability to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
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.
Arms & Interventions
Sequence AB
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.
Intervention: Rosuvastatin (Drug)
Sequence AB
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.
Intervention: Macitentan (Drug)
Outcomes
Primary Outcomes
Cmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
Time Frame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
Cmax is the maximum observed plasma concentration and is directly derived from the individual plasma concentration time curves of rosuvastatin
AUC(0-inf) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)
Time Frame: From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17)
AUC(0-inf) is the area under the plasma concentration-time curves of rosuvastatin, calculated from time zero to the extrapolated infinite time
Secondary Outcomes
- AUC(0-t) of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)(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)(From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17))
- Change from baseline in supine blood pressure(From Day1 to end-of-study visit (Day 26-28))
- Change from baseline in ECG variables(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)(From Day1 to follow-up period (Day46-48))
- tmax of rosuvastatin following administration of rosuvastatin alone (treatment A) and in combination with macitentan (treatment B)(From Day1 to Day17 (treatment A: from Day1-Day5 and treatment B: from Day10-Day17))
- Change from baseline in pulse rate(From Day1 to end-of-study visit (Day 26-28))
- Change from baseline in heart rate (HR)(From Day1 to end-of-study visit (Day 26-28))
- Change from baseline to end-of-study (EOS) in body weight(From Day1 to end-of-study visit (Day 26-28))
- Change from baseline in clinical laboratory tests(From Day1 to end-of-study visit (Day 26-28))
- Trough plasma concentrations of macitentan and its metabolite ACT-132577(From Day5 to Day17)