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

NCT04991207 | Completed Phase 1

• 2 other identifiers: BIA-51058-1072015-004350-17
• Study Type: interventional
• Target: 44
• 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 PK of bosentan.
• To assess the effect of bosentan 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 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 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 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 bosentan)

  PK parameters were determined for bosentan and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of bosentan 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 bosentan)

  PK parameters were determined for bosentan and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of bosentan 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 bosentan)

  PK parameters were determined for bosentan and metabolites in plasma following multiple dose administration in Treatment Period 2 and Treatment Period 3. Samples for PK assessments of bosentan 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. 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

Bosentan

ACTIVE COMPARATOR

Treatment Period 2: Subjects were admitted to the clinical unit on Day 1. Subjects received multiple (twice daily \[b.i.d.\]) oral doses of bosentan (Tracleer® 1 x 125 mg film coated tablet) approximately 30 minutes before each meal (breakfast 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 bosentan (Tracleer® 1 x 125 mg film coated tablet). 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: bosentan

BIA 5-1058 and Bosentan

EXPERIMENTAL

Treatment Period 3: Subjects were admitted to the clinical unit on Day 1. Subjects received multiple b.i.d. oral doses of bosentan (Tracleer® 1 x 125 mg film coated tablet) approximately 30 minutes before each meal (breakfast 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 bosentan (Tracleer® 1 x 125 mg film coated tablet). 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: bosentan

Interventions

BIA 5-1058 DRUG

Oral BIA 5-1058 (Zamicastat) 100 mg tablets

Also known as: Zamicastat

BIA 5-1058; BIA 5-1058 and Bosentan

bosentan DRUG

Oral Tracleer (bosentan) 125 mg film coated tablets

Also known as: Tracleer

BIA 5-1058 and Bosentan; Bosentan

Eligibility Criteria

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

You may 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) 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.

You may not qualify if:

• 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.
• 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 enrollment 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 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.

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; Bosentan

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

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 28, 2021
• First Posted: August 5, 2021
• Study Start: February 6, 2018
• Primary Completion: May 14, 2018
• Study Completion: May 14, 2018
• Last Updated: August 5, 2021

Record last verified: 2021-07

Locations

DE (1)