Pulmonary Arterial Hypertension
Conditions
Brief summary
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
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).
Interventions
DRUGBIA 5-1058
Oral BIA 5-1058 (Zamicastat) 100 mg tablets
DRUGSildenafil
Oral Sildenafil ( Revatio) 20 mg film coated tablets
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provided signed and dated informed consent before any study specific procedures were conducted. 2. Male and female subjects aged 18 to 45 years (both inclusive) at the Screening Visit. 3. 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. 4. Non-smoker or ex-smoker for at least 3 months prior to the Screening Visit. 5. 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. 6. 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. 7. Negative screen for alcohol and drugs of abuse at the Screening Visit and on admission to each treatment period. 8. 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. 9. 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: 1. Provided signed and dated informed consent before any study specific procedures were conducted. 2. Male and female subjects aged 18 to 45 years (both inclusive) at the Screening Visit. 3. 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. 4. Non-smoker or ex-smoker for at least 3 months prior to the Screening Visit. 5. 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. 6. 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. 7. Negative screen for alcohol and drugs of abuse at the Screening Visit and on admission to each treatment period. 8. 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. 9. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - Maximum observed concentration (for BIA 5-1058) | Up to 2 months and 3 weeks | 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) |
| Tmax - Time corresponding to occurrence of Cmax (for BIA 5-1058) | Up to 2 months and 3 weeks | 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) |
| T½ - Apparent terminal elimination half life (for BIA 5-1058) | Up to 2 months and 3 weeks | 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) |
| Cmax,ss - Maximum observed concentration at steady state (for sildenafi) | Up to 2 months and 3 weeks | 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) |
| Tmax,ss - Time corresponding to occurrence of Cmax,ss at steady state (for sildenafi) | Up to 2 months and 3 weeks | 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) |
| T½,ss - Apparent terminal elimination half-life at steady state (for sildenafi) | Up to 2 months and 3 weeks | 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) |
Countries
Germany
Outcome results
None listed