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

Study Overview
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Brief Summary
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The purpose of this study is: To assess the effect of BIA 5 1058 400 mg on the pharmacokinetics (PK) of sildenafil. To assess the effect of sildenafil on the PK of BIA 5-1058.

Detailed Description
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This study was an open label, three period, fixed sequence study in healthy male and female subjects performed under fasting conditions at a single study center. The study comprised: Screening during Days -28 to -2 (both inclusive). Three treatment periods separated by a washout period of at least 10 days. Duration of Treatment: The duration of participation for each subject was approximately 2 months and 3 weeks (including the screening period).

Official Title
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An Open-Label, Three Period, Fixed Sequence Study to Assess the Effect of a Single Dose of BIA 5-1058 400 mg on the Steady State Pharmacokinetics of Sildenafil in Healthy Subjects Under Fasting Conditions

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: BIA 5-1058
* Drug: Sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) antibody to anti-HBc (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. The subject had to be willing and able to be confined to the clinical unit and had to adhere to the study and lifestyle restrictions. Contraception requirements: 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: 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) antibody to anti-HBc (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. The subject had to be willing and able to be confined to the clinical unit and had to adhere to the study and lifestyle restrictions. Contraception requirements: 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: Subjects who met any of the following criteria were not considered eligible to participate/continue in the study: 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 investigational medicinal product (IMP) administration. 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. Clinically relevant surgical history involving the stomach and/or intestinal system, potentially affecting absorption of IMPs. 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 enrolment to rule out laboratory error. 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. History of relevant atopy or drug hypersensitivity. History of alcoholism or drug abuse. 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. Use of alcohol within 72 hours before the Screening Visit and from 48 hours before dosing until completion of the Follow-up Visit. Significant infection or known inflammatory process at the Screening Visit or upon admission to all treatment periods, as judged by the Principal Investigator. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, heartburn) at the time of the Screening Visit or upon admission to all treatment periods. Subjects with supine 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 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. Abnormal fundoscopy. Electrocardiogram (mean of triplicate) with QTcF > 450 ms at the Screening Visit or admission to the first treatment period. 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 1.73 m2. Previous use of BIA 5-1058. Use of any investigational drug or participation in any study within 60 days or 5 half-life times, whichever was longer, before first administration of IMP. Having received IMP in more than 3 studies within 12 months before the Screening Visit. Donated or received blood within 56 days before first administration of IMP. Donated or received plasma within 30 days before first administration of IMP. History of any significant bleeding within the last 56 days prior to first administration of IMP. Vegetarians, vegans or other medical dietary restrictions. Not able to communicate reliably with the Principal Investigator. Unlikely to comply with the requirements of the study. 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/paracetamol1000 mg/day was permitted. CYP2B6, CYP2C8, CYP2D6, CYP3A4 (BIA 5-1058 metabolism) and CYP2C9, CYP3A4 (sildenafil metabolism): Use of inhibitors taken within 7 days before the first IMP administration and inducers taken within 28 days before first IMP administration. Any known allergy or contra-indication to any of the IMPs or their content. 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. 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: Pregnant or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIA 5-1058<br>Treatment Period 1: Subjects were admitted to the clinical unit on Day 1. Subjects received a single oral dose of BIA 5 1058 400 mg (4 x 100 mg tablets) on Day 1 after an overnight fast of at least 8 hours and remained fasted for at least 4 hours post-dose. Subjects were discharged from the clinical unit on Day 4 (approximately 72 hours after dosing) barring any medical reasons for an extended clinical stay. | Drug: BIA 5-1058<br>* Oral BIA 5-1058 (Zamicastat) 100 mg tablets<br>* Other names: Zamicastat;|
| Active Comparator: Sildenafil<br>Treatment Period 2: Subjects were admitted to the clinical unit on Day 1. Subjects received multiple three times a day (t.i.d.) oral doses of sildenafil (Revatio® 1 x 20 mg film coated tablet) approximately 2 hours before or after each meal (breakfast, lunch and dinner) from Days 1 to 5. On Day 6 after an overnight fast of at least 8 hours, subjects received a single morning dose of sildenafil (Revatio® 1 x 20 mg film coated tablet) and remained fasted for at least 2 hours post-dose. Subjects were discharged from the clinical unit on Day 9 (approximately 72 hours after last dosing) barring any medical reasons for an extended clinical stay. | Drug: Sildenafil<br>* Oral Sildenafil ( Revatio) 20 mg film coated tablets<br>* Other names: Revatio;|
| Experimental: BIA 5-1058 and Sildenafil<br>Treatment Period 3: Subjects were admitted to the clinical unit on Day 1. Subjects received multiple t.i.d. oral doses of sildenafil (Revatio® 1 x 20 mg film coated tablet) approximately 2 hours before or after each meal (breakfast, lunch and dinner) from Days 1 to 5. On Day 6 after an overnight fast of at least 8 hours, subjects received a single concomitant dose of BIA 5-1058 400 mg (4 x 100 mg tablets) and sildenafil (Revatio® 1 x 20 mg film coated tablet) and remained fasted for at least 4 hours post-dose. Subjects were discharged from the clinical unit on Day 9 (approximately 72 hours after last dosing) barring any medical reasons for an extended clinical stay. | Drug: BIA 5-1058<br>* Oral BIA 5-1058 (Zamicastat) 100 mg tablets<br>* Other names: Zamicastat;Drug: Sildenafil<br>* Oral Sildenafil ( Revatio) 20 mg film coated tablets<br>* Other names: Revatio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax - Maximum observed concentration (for BIA 5-1058) | PK parameters were determined for BIA 5-1058 and its metabolites in plasma following single dose administration in Treatment Period 1 and Treatment Period 3. Samples for PK assessments of BIA 5 1058 and metabolites were collected at pre-dose (Treatment Period 1, Day 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples); and at pre-dose (Treatment Period 3, Day 6) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks | 
| Tmax - Time corresponding to occurrence of Cmax (for BIA 5-1058) | PK parameters were determined for BIA 5-1058 and its metabolites in plasma following single dose administration in Treatment Period 1 and Treatment Period 3. Samples for PK assessments of BIA 5 1058 and metabolites were collected at pre-dose (Treatment Period 1, Day 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples); and at pre-dose (Treatment Period 3, Day 6) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks | 
| T½ - Apparent terminal elimination half life (for BIA 5-1058) | PK parameters were determined for BIA 5-1058 and its metabolites in plasma following single dose administration in Treatment Period 1 and Treatment Period 3. Samples for PK assessments of BIA 5 1058 and metabolites were collected at pre-dose (Treatment Period 1, Day 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples); and at pre-dose (Treatment Period 3, Day 6) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks | 
| Cmax,ss - Maximum observed concentration at steady state (for sildenafi) | PK parameters were determined for sildenafi and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of sildenafil and metabolites were collected at pre-last dose (Treatment Period 2, Day 6 and Treatment Period 3, Day 6) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks | 
| Tmax,ss - Time corresponding to occurrence of Cmax,ss at steady state (for sildenafi) | PK parameters were determined for sildenafi and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of sildenafil and metabolites were collected at pre-last dose (Treatment Period 2, Day 6 and Treatment Period 3, Day 6) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks | 
| T½,ss - Apparent terminal elimination half-life at steady state (for sildenafi) | PK parameters were determined for sildenafi and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of sildenafil and metabolites were collected at pre-last dose (Treatment Period 2, Day 6 and Treatment Period 3, Day 6) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples) | Up to 2 months and 3 weeks |