Effect of BIA 5-1058 400 mg on Warfarin Pharmacokinetics

NCT04994119 | Completed Phase 1

• 2 other identifiers: BIA-51058-1092015-004351-49
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is:

• To investigate CYP2C9 inhibition by BIA 5-1058 through the assessment of its effect on the Pharmacokinetic (PK) of S-warfarin, a substrate of CYP2C9.
• To assess the effect of warfarin on the PK of BIA 5-1058.

Conditions

Pulmonary Arterial Hypertension

Outcome Measures

Primary Outcomes (3)

• Cmax - Maximum observed concentration

  Primary Pharmacokinetic Parameters: 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 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples). Samples for PK assessments of warfarin were collected at pre-dose (Treatment Period 2, Day 1 and Treatment Period 3, Day 1) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours (18 samples)

  Up to 2 months and 2 weeks

• AUC0-t - Area under the plasma concentration-time curve (AUC) from time zero to the last quantifiable concentration

  Primary Pharmacokinetic Parameters: 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 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples). Samples for PK assessments of warfarin were collected at pre-dose (Treatment Period 2, Day 1 and Treatment Period 3, Day 1) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours (18 samples)

  Up to 2 months and 2 weeks

• AUC0-inf - AUC from time zero extrapolated to infinity

  Primary Pharmacokinetic Parameters: 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 1) and post-dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours (15 samples). Samples for PK assessments of warfarin were collected at pre-dose (Treatment Period 2, Day 1 and Treatment Period 3, Day 1) and post-last dose at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 hours (18 samples)

  Up to 2 months and 2 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

Warfarin

EXPERIMENTAL

Treatment Period 2: Subjects were admitted to the clinical unit on Day 1. Subjects received a single dose of racemic warfarin (Coumadin® 5 x 5 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. Subjects were required to return for out patient visits.

Drug: Warfarin

BIA 5-1058 and Warfarin

EXPERIMENTAL

Treatment Period 3: Subjects were admitted to the clinical unit on Day 1. Subjects received a single concomitant dose of BIA 5-1058 400 mg (4 x 100 mg tablets) and racemic warfarin (Coumadin® 5 x 5 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. Subjects were required to return for out patient visits.

Drug: BIA 5-1058; Drug: Warfarin

Interventions

BIA 5-1058 DRUG

Oral BIA 5-1058 (Zamicastat) 100 mg tablets

Also known as: Zamicastat

BIA 5-1058; BIA 5-1058 and Warfarin

Warfarin DRUG

Oral Warfarin (Coumadin) 5 mg film coated tablets

Also known as: Coumadin

BIA 5-1058 and Warfarin; Warfarin

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.
• 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 meeting 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 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; Warfarin

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; 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: February 23, 2018
• Primary Completion: May 23, 2018
• Study Completion: May 23, 2018
• Last Updated: August 6, 2021

Record last verified: 2021-07

Locations

DE (1)