Effect of Age-gender on the Pharmacokinetic and Pharmacodynamic Profiles of BIA 5 1058

Effect of Age-gender on the Pharmacokinetic and Pharmacodynamic Profiles of BIA 5 1058. An Open-label, Parallel Group, Multiple Dose 10-day Study.

the purpose of this study is to determine the effect of age on the Pharmacokinetics (PK) profile of BIA 5-1058 at steady state after multiple oral doses

Study Overview

• Status: Terminated
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: BIA 5-1058

Detailed Description

This was a single-centre, open-label, parallel group, non-randomised, two-part multiple dose 10-day study in healthy young and elderly male and female subjects. The study comprised a screening evaluation between 2 and 28 days before the first Investigational Medicinal Product (IMP) administration, a hospitalisation period of 15 days comprising a treatment period of 10 days, and a follow-up visit approximately 7 days after discharge.

Part 1: Subjects received 1200 mg of BIA 5-1058 once a day (od), in fasting conditions, for 10 days Part 2 : Subjects received 400 mg of BIA 5-1058 od, in fasting conditions, for 10 days.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All subjects (young and elderly):

1. A signed and dated informed consent form before any study-specific screening procedure was performed;
2. Healthy male and female subjects as determined by the Investigator on the basis of medical history, physical examination, clinical laboratory test results, vital signs and digital 12-lead electrocardiogram (ECG);
3. Non-smoker or ex-smokers for at least 3 months at screening;
4. BMI between 18 and 30 kg/m2, inclusive;
5. Negative tests for hepatitis B surface antigen (HBsAg), anti-hepatitis C virus antibodies (HCV Ab) and anti-human immunodeficiency virus antibodies (HIV-1 and HIV-2 Ab) at screening;
6. Clinical laboratory test results clinically acceptable at screening and admission to the study;

7. Negative screen for alcohol and drugs of abuse at screening and admission to the study;

   If male:

8. Using an effective method of contraception with a pregnant partner or partner of childbearing potential (condom or occlusive cap [diaphragm or cervical or vault caps] with spermicidal foam or gel or film or cream or suppository; true abstinence; or vasectomy) throughout the study;

9. Refraining from donating sperm throughout the study.

   Young subjects only:

10. Males and females aged between 18 and 40 years, inclusive.

    If female:

11. No childbearing potential by reason of surgery or at least 1 year post-menopause (i.e., 12 months post last menstrual period), or menopause confirmed by follicle-stimulating hormone (FSH) testing;
12. If of childbearing potential, using an effective non-hormonal method of contraception [intrauterine device or intrauterine system; condom or occlusive cap (diaphragm or cervical or vault caps) with spermicidal foam or gel or film or cream or suppository; true abstinence; or vasectomized male partner, provided that he is the sole partner of that subject] for all the duration of the study;

13. If of childbearing potential, negative serum pregnancy test at screening and negative urine pregnancy test on admission to the study.

    Elderly subjects only:

14. Males and females older than 65 years, inclusive.

Exclusion Criteria:

All subjects (young and elderly):

1. Clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, haematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, endocrine, connective tissue diseases or disorders;
2. Clinically relevant surgical history;
3. History of relevant atopy or drug hypersensitivity;
4. History of alcoholism or drug abuse;
5. Consumption of more than 14 units of alcohol a week [1 unit corresponds to 1 glass of 12° wine (10 cL), 1 glass of 45° pastis (2.5 cL), 1 glass of 40° whisky (2.5 cL), 1 glass of 12° champagne (10 cL), 1 glass of 18°aperitif drink (7 cL) or one 25-cL glass of 5°beer];
6. Significant infection or known inflammatory process at screening or admission to study;
7. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea, heartburn) at the time of screening or admission to the study;
8. Previous use of BIA 5-1058;
9. Use of any investigational drug or participation in any clinical trial within 90 days prior to screening;
10. Participation in more than 2 clinical trials within the 12 months prior to screening;
11. Donation or reception of any blood or blood products within the 3 months prior to screening;
12. Vegetarians, vegans or other medical dietary restrictions;
13. Not able to communicate reliably with the Investigator;

14. Unlikely to co-operate with the requirements of the study.

    If male:

15. Not using an accepted effective method of contraception;

16. Refusing to refrain from donating sperm throughout the study.

    Young subjects only:

17. Use of medicines within 2 weeks of admission that could affect the safety or other study assessments, in the Investigator's opinion;

    If female of childbearing potential:

18. Pregnant or breastfeeding;

19. Not using an accepted effective contraceptive method or using oral contraceptives.

    Elderly subjects only:

20. For elderly subjects, previously prescribed medications that interfered with absorption, distribution, metabolism, and excretion or safety/tolerability evaluation of BIA 5-1058 and adrenal or renal function were prohibited; however, previously prescribed medications that did not interfere with absorption, distribution, metabolism, and excretion or safety/tolerability evaluation of BIA 5-1058, adrenal or renal function and which could not interfere with the objectives of the study were allowed if the dose regimen had been stable for at least 4 weeks and was expected to remain stable throughout the study. Such concomitant medications were to be reviewed and mutually agreed upon by the Sponsor and the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BIA 5-1058 1200 mg (Part I); Subjects received 1200 mg of BIA 5-1058 once a day (od), in fasting conditions, for 10 days	Drug: BIA 5-1058; Each subject was administered either 1200 mg (Part 1) or 400 mg (Part 2) BIA 5-1058 od for 10 days, in fasting conditions for 8 hours [Day (D)2 to D9] or 10 hours (D1 and D13), and remained fasted for 2 hours (D2 to D9) or 4 hours (D1 and D13) post-dose. The formulation was tablets 100 mg and the mode of administration was oral.; Other Names: Zamicastat
Experimental: BIA 5-1058 400 mg (Part II); Subjects received 400 mg of BIA 5-1058 od, in fasting conditions, for 10 days.	Drug: BIA 5-1058; Each subject was administered either 1200 mg (Part 1) or 400 mg (Part 2) BIA 5-1058 od for 10 days, in fasting conditions for 8 hours [Day (D)2 to D9] or 10 hours (D1 and D13), and remained fasted for 2 hours (D2 to D9) or 4 hours (D1 and D13) post-dose. The formulation was tablets 100 mg and the mode of administration was oral.; Other Names: Zamicastat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed plasma concentration (Cmax)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks
Time of occurrence of Cmax (tmax)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks
Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time at which the drug concentration was at or above the lower limit of quantification (AUC0-t)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks
Area under the plasma concentration-time curve from time zero to 24 hours after last dosing (AUC0-24)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks
Apparent terminal half-life (t½)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks
Apparent total body clearance (CL/F)	Pharmacokinetic analysis Blood samples for PK analysis were taken at the following times: On D1: before BIA 5-1058 dosing (pre-dose), and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 h post-dose (before the second administration on D2). On D3, D7, D8 and D9: before BIA 5-1058 dosing. From D10 to D13: before BIA 5-1058 dosing, and 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24 (D11), 36 (D11), 48 (D12), 60 (D12) and 72h post-dose (D13).	Up to 4 weeks

Collaborators and Investigators

• Sponsor: Bial - Portela C S.A.

Study record dates

Study Major Dates

• Study Start (Actual): October 12, 2015
• Primary Completion (Actual): December 30, 2016
• Study Completion (Actual): December 30, 2016

Study Registration Dates

• First Submitted: July 28, 2021
• First Submitted That Met QC Criteria: July 28, 2021
• First Posted (Actual): August 5, 2021

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 28, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Zamicastat
• Other Study ID Numbers: BIA-51058-105; 2015-003682-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No