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

NCT04994860 | Completed Phase 1

• 2 other identifiers: BIA-51058-1082017-000224-99
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (3)

BIA 5-1058

EXPERIMENTAL

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

Sildenafil

ACTIVE COMPARATOR

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

BIA 5-1058 and Sildenafil

EXPERIMENTAL

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; Drug: Sildenafil

Interventions

BIA 5-1058 DRUG

Oral BIA 5-1058 (Zamicastat) 100 mg tablets

Also known as: Zamicastat

BIA 5-1058; BIA 5-1058 and Sildenafil

Sildenafil DRUG

Oral Sildenafil ( Revatio) 20 mg film coated tablets

Also known as: Revatio

BIA 5-1058 and Sildenafil; Sildenafil

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Bial - Portela C S.A.: lead

Study Sites (1)

PAREXEL International - Early Phase Clinical Unit - Berlin

Berlin, 14050, Germany

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

zamicastat; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 29, 2021
• First Posted: August 6, 2021
• Study Start: March 22, 2018
• Primary Completion: June 7, 2018
• Study Completion: June 7, 2018
• Last Updated: August 6, 2021

Record last verified: 2021-07

Locations

DE (1)