Effect of BIA 5-1058 400 mg on the Steady State Pharmacokinetics of Bosentan

Inclusion Criteria: Subjects who met the following criteria were considered eligible to participate/continue in the study: * Provided signed and dated informed consent before any study specific procedures were conducted. * Male and female subjects aged 18 to 45 years (both inclusive) at the Screening Visit. * Healthy as determined by the Principal Investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs and digital 12 lead electrocardiogram (ECG). If a vital sign or ECG assessment was outside of the reference range at the Screening Visit or baseline, the assessment could have been repeated once as soon as possible and in any cases before enrollment to rule out any error. * Non-smoker or ex-smoker for at least 3 months prior to the Screening Visit. * Body mass index (BMI) between 18.5 and 29.9 kg/m2 (both inclusive) at the Screening Visit and on admission to each treatment period. * Negative test results for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti HBc), immunoglobulin M (IgM) anti-HBc, hepatitis C virus antibody (anti HCV) and human immunodeficiency virus (HIV) (Types 1 and 2) antibodies at the Screening Visit. * Negative screen for alcohol and drugs of abuse at the Screening Visit and on admission to each treatment period. * Subject had to be willing and able to be confined to the clinical unit and had to adhere to the study and lifestyle restrictions. * Male subjects had to use together with his female partner/spouse a highly effective contraception form of birth control in combination with a barrier method throughout the clinical study period. And agreed not to father a child or to donate sperm starting at the Screening Visit and throughout the clinical study. * Female subjects had to either be of non childbearing potential or had to use highly effective methods of contraception from at least 3 months before the Screening Visit and throughout the clinical study in combination with a barrier method. Exclusion Criteria: 1. Clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue disease or disorders within 5 years before the first IMP administration. 2. Documented coronary artery disease (any of prior myocardial infarction, positive stress test, positive nuclear perfusion study, prior coronary artery bypass graft \[CABG\] surgery or percutaneous coronary intervention, angiogram showing at least 75% stenosis in a major coronary artery), acute coronary syndrome or current symptoms of myocardial ischemia and angina. 3. Clinically relevant surgical history involving the stomach and/or intestinal system, potentially affecting absorption of IMPs. 4. Any clinically relevant findings in the laboratory tests, particularly any abnormality in the coagulation tests or the liver function tests, as judged by the Principal Investigator, at the Screening Visit and on admission to each treatment period. If a laboratory assessment was outside of the reference range at the local laboratory at the Screening Visit or baseline, the assessment could have been repeated once as soon as possible and in any cases before enrollment to rule out laboratory error. 5. Subjects with alanine aminotransferase (ALT) \> 1.0 x the upper limit of normal (ULN) and/or aspartate aminotransferase (AST) \> 1.0 x ULN and/or total bilirubin \> 1.0 x ULN (isolated bilirubin \> 1.0 x ULN and 1.5 x ULN was acceptable if bilirubin was fractionated and direct bilirubin \< 35%), as confirmed by subsequent repeat assessment, at the Screening Visit and on admission to each treatment period. 6. History of relevant atopy or drug hypersensitivity. 7. History of alcoholism or drug abuse. 8. History of drinking \> 24 g (males) and \> 12 g (females) of pure alcohol per day (10 g pure alcohol = 250 mL of beer \[5%\] or 35 mL of spirits \[35%\] or 100 mL of wine \[12%\]) within 3 months before first admission to the clinical unit. 9. Use of alcohol within 72 hours before the Screening Visit and from 48 hours before dosing until completion of the Follow-up Visit. 10. Significant infection or known inflammatory process at the Screening Visit or upon admission to all treatment periods, as judged by the Principal Investigator. 11. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, heartburn) at the time of the Screening Visit or upon admission to all treatment periods. 12. Subjects with blood pressure (BP) measurements (mean of triplicate) outside the ranges, at the Screening Visit or admission to the first treatment period: * Systolic BP (SBP) \< 100 mmHg or \> 140 mmHg * Diastolic BP (DBP) \< 60 mmHg or \> 90 mmHg 13. Symptomatic orthostatic hypotension (drop of \> 20 mmHg in SBP and/or \> 10 mmHg in DBP when moving from supine to standing position), together with other symptoms, e.g., dizziness, at the Screening Visit or admission to the first treatment period. 14. Abnormal fundoscopy. 15. Electrocardiogram (mean of triplicate) with corrected QT interval using the Fridericia's formula (QTcF) \> 450 ms at the Screening Visit or admission to the first treatment period. 16. Having an estimated glomerular filtration rate (eGFR) \< 90 mL/min, based on creatinine clearance calculation by the Cockcroft Gault formula and normalized to an average surface area of 1.73m2. 17. Previous use of BIA 5 1058. 18. Use of any investigational drug or participation in any clinical study within 60 days or 5 half life times, whichever was longer, before first administration of IMP. 19. Having received IMP in more than 3 studies within 12 months before the Screening Visit. 20. Donated or received blood within 56 days before first administration of IMP. 21. Donated or received plasma within 30 days before first administration of IMP. 22. History of any significant bleeding within the last 56 days prior to first administration of IMP. 23. Vegetarians, vegans or other medical dietary restrictions. 24. Not able to communicate reliably with the Principal Investigator. 25. Unlikely to comply with the requirements of the study. 26. Use of over the counter (OTC) medications (including oral natural health products, vitamin and herbal supplements) within 7 days before the first IMP administration until the Follow up Visit. Use of prescription medications that could have affected the safety or other study assessments, in the Principal Investigator's opinion, within 14 days before the first IMP administration until the Follow-up Visit. By exception, acetaminophen/paracetamol 1000 mg/day was permitted. CYP2B6, CYP2C8, CYP2D6, CYP3A4 (BIA 5-1058 metabolism) and CYP2C9, CYP2C19, CYP3A4 (bosentan metabolism): Use of inhibitors taken within 7 days before the first IMP administration and inducers taken within 28 days before first IMP administration. 27. Any known allergy or contra-indication to any of the IMPs or their content. 28. The subject was an employee or the close relative of an employee of the Sponsor or the Contract Research Organization (CRO) involved in the clinical study. 29. Vulnerable subjects, e.g., subjects kept in detention, protected adults under guardianship, trusteeship and soldiers or subjects committed to an institution by governmental or juridical order. If female: 30. Pregnant or breast-feeding.