Healthy Subjects
Conditions
Keywords
macitentan, rosuvastatin, pharmacokinetics
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.
Interventions
DRUGRosuvastatin
Single oral dose of 10 mg rosuvastatin (film-coated tablet) on Day 1 and Day 10
DRUGMacitentan
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
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-inf) 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) | AUC(0-inf) is the area under the plasma concentration-time curves of rosuvastatin, calculated from time zero to the extrapolated infinite time |
| Cmax 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) | Cmax is the maximum observed plasma concentration and is directly derived from the individual plasma concentration time curves of rosuvastatin |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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 |
| Trough plasma concentrations of macitentan and its metabolite ACT-132577 | From Day5 to Day17 | Trough concentrations of macitentan and ACT-132577 are measured before oral administration of macitentan |
| Change from baseline in supine blood pressure | From Day1 to end-of-study visit (Day 26-28) | Change from baseline to each time point of measurement during study period |
| Change from baseline in pulse rate | From Day1 to end-of-study visit (Day 26-28) | Change from baseline to each time point of measurement during study period |
| 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) | The time to reach maximum plasma concentration (tmax) of rosuvastatin |
| Change from baseline in ECG variables | From Day1 to end-of-study visit (Day 26-28) | 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) |
| Change from baseline to end-of-study (EOS) in body weight | From Day1 to end-of-study visit (Day 26-28) | Change in body weight measured in kg during study period |
| Change from baseline in clinical laboratory tests | From Day1 to end-of-study visit (Day 26-28) | Change from baseline to each time point of measurement during study period for clinical laboratory tests (hematology, clinical chemistry, serology) |
| Incidence rate of treatment-emergent treatment-emergent adverse events (AEs) and serious adverse events (SAEs) | From Day1 to follow-up period (Day46-48) | 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. |
| Change from baseline in heart rate (HR) | From Day1 to end-of-study visit (Day 26-28) | Change from baseline to each time point of measurement during study period |
| 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) | 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 |
Countries
Germany
Outcome results
None listed