Pulmonary Arterial Hypertension
Conditions
Keywords
PAH, BIA 5-1058, Zamicastat, Bial, Bial - Portela & Ca, S.A., dopamine ß-hydroxylase (DßH) inhibitor, vascular obstruction, pulmonary arteries, right-heart catheterisation (RHC), idiopathic, rare lung disease
Brief summary
This Study evaluates the pharmacokinetic (PK) profile of different zamicastat doses in Pulmonary arterial hypertension (PAH) patients to find the most promising therapeutic dosage range for the treatment of PAH disease
Detailed description
This is an open-label, multi-centre study in patients with PAH who are currently on stable treatment with at least one PAH medication. It is planned to evaluate the PK profile (24 hour profile and trough levels) and the safety, tolerability and efficacy of four different zamicastat doses. Each patient will start treatment with the lowest dose (50 mg zamicastat once daily) and the dose will be up-titrated to the individual highest tolerated dose (HTD) i.e. up to 200 mg zamicastat once daily. A data safety monitoring board (DSMB) will periodically review the safety data and will issue a recommendation if the doses can be used as planned. This study will consist of: * A screening period, 5 to 12 days: visit V1 * Up to four dose finding periods, 14 days each: * Dose A (50 mg zamicastat once daily): visits A1, A2 and A3 * Dose B (100 mg zamicastat once daily): visits B2 and B3 * Dose C (150 mg zamicastat once daily): visits C2 and C3 * Dose D (200 mg zamicastat once daily): visits D2 and D3 * Maintenance period, 42 days: maintenance period visit (MPV)1, MPV2 and MPV3 * Follow-up (FU) period, 14 to 28 days: visits FU (down-titration) and FU
Interventions
DRUGOral zamicastat
Tablets for oral administration under fed conditions containing 100 mg of zamicastat
Sponsors
Bial - Portela C S.A.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female patients aged 18 to 70 years. 2. Able to comprehend and willing to sign an informed consent form. 3. Diagnosis of PAH (pulmonary arterial hypertension WHO Group 1), documented by right heart catheterisation with a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, a pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance (PVR) \> 3 wood unit (WU): 1. Idiopathic, in non-vasoreactive patients 2. Heritable: Bone morphogenetic protein receptor type II (BMPR2) mutation and other mutations, in non-vasoreactive patients 3. Drugs and toxin induced, in non-vasoreactive patients 4. Associated with connective tissue disease 5. Associated with simple congenital defects (atrial septal defect and/or ventricular septal defect) if closed \> 12 months before inclusion. 4. World Health Organization (WHO) functional class II or III as judged by the investigator. 5. Stable treatment with at least one of the following approved PAH therapies for at least 90 days prior to V1: Ambrisentan, Bosentan, Macitentan, Riociguat, Selexipag, Sildenafil, Tadalafil, Epoprostenol intravenous, Iloprost inhaled or Treprostinil intravenous or subcutaneous.
Exclusion criteria
1. Contraindication to zamicastat, i.e. known hypersensitivity to ingredients of zamicastat formulation. 2. Two or more consecutive measurements of systolic blood pressure (SBP) \< 95 mmHg or diastolic blood pressure (DBP) \< 50 mmHg. 3. Uncontrolled diabetes mellitus with HbA1c ≥ 8.5% within the last three months or at screening. 4. PAH WHO Group 1 due to portal hypertension, human immunodeficiency virus (HIV) infection and schistosomiasis. 5. Any disease known to cause pulmonary hypertension other than PAH WHO Group 1. 6. Obstructive lung disease: Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) \< 60% and FEV1 \< 60% of predicted value after bronchodilator administration. 7. Restrictive lung disease: Total Lung Capacity (TLC) \< 70% of predicted value. 8. History of moderate to severe hepatic impairment (Child-Pugh B and C). 9. Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 (measured at V1). 10. Use of the following prohibited medication or treatments during study participation: calcium channel blockers (CCBs) if used for the treatment of PAH in vasoreactive patients; drugs containing a catechol group that is metabolised by dopamine ß-hydroxylase (DβH) e.g. rimiterole, isoprenaline, dopamine, dopexamine or dobutamide or α- and/or β-blockers. 11. Current or previous (within the past year) alcohol or substance abuse excluding caffeine or nicotine. 12. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the study treatment or may jeopardise the patient's safety, compliance or adherence to protocol requirements. 13. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice acceptable contraceptive measures from the time of informed consent until 30 days after last investigational medicinal product (IMP) intake. Acceptable methods for women are surgical intervention (e.g. bilateral tubal occlusion), non-hormonal implantable intrauterine device, double-barrier methods, true sexual abstinence (i.e. when this is in line with the preferred and usual lifestyle of the patient) and vasectomised partner (provided that the partner is the sole sexual partner of the patient and the partner has received medical assessment of the surgical success). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), hormonal contraceptives and withdrawal are not acceptable methods of contraception. For men: Male patients who are sexually active with a partner of childbearing potential must use, with their partner, a condom plus an approved acceptable contraceptive measure from the time of informed consent until 90 days after the last IMP intake. The following methods are acceptable methods of contraception: partner's use of combined (oestrogen and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); partner's use of progestogen-only hormonal contraception (oral, injectable/implantable, intrauterine hormone-releasing system); partner's use of implantable intrauterine device; surgical sterilisation (for example, vasectomy or bilateral tubal occlusion). 14. Previous participation in any other drug investigational study within the past 30 days (or five half-lives of IMP whichever is longer) prior to V1. 15. Vulnerable patients according to Section 1.61 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline for Good Clinical Practice E6.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after investigational medicinal product (IMP) intake) | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat |
| Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | 1, 2, 4, 8, 16 and 24 hours after IMP intake | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) |
| Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat |
| Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | 1, 2, 4, 8, 16 and 24 hours after IMP intake | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) |
| Time Until Cmax (Tmax) (h) - 50 mg | Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake) | This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat |
| Time Until Cmax (Tmax) (h) - HTD | 1, 2, 4, 8, 16 and 24 hours after IMP intake | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD) |
| Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | 1, 2, 4, 8, 16 and 24 hours after IMP intake | This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD). Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data. |
Countries
Austria, Germany, Italy, Portugal, Spain, Ukraine, United Kingdom
Participant flow
Pre-assignment details
Of 33 patients enrolled in this study, 29 patients started treatment with zamicastat (4 Screening Failures), 28 patients completed the dose finding period and entered the maintenance period (1 premature termination). Patients who had been enrolled and, for whatever reason, discontinued the study after first IMP intake at visit A1 were classified as withdrawals. Patients might withdraw from the study at any time, either on their own request or at the discretion of the investigator.
Participants by arm
| Arm | Count |
|---|---|
| 50 mg Zamicastat 50 mg zamicastat once daily (half a tablet of 100 mg)
Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 1 |
| 100 mg Zamicastat Once Daily 100 mg zamicastat once daily (one tablet of 100 mg)
Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 6 |
| 150 mg Zamicastat Once Daily 150 mg zamicastat once daily (one and a half tablet of 100 mg)
Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 2 |
| 200 mg Zamicastat Once Daily 200 mg zamicastat once daily (two tablets of 100 mg)
Zamicastat: Tablets for oral administration under fed conditions containing 100 mg of zamicastat (BIA 5-1058) | 19 |
| Total | 28 |
Baseline characteristics
| Characteristic | 50 mg Zamicastat | 100 mg Zamicastat Once Daily | 150 mg Zamicastat Once Daily | 200 mg Zamicastat Once Daily | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 6 Participants | 2 Participants | 16 Participants | 25 Participants |
| BMI (kg/m2) <=25,4kg/m2 | 0 Participants | 4 Participants | 2 Participants | 9 Participants | 15 Participants |
| BMI (kg/m2) >=25,5kg/m2 | 1 Participants | 2 Participants | 0 Participants | 10 Participants | 13 Participants |
| Childbearing Potential No | 1 Participants | 2 Participants | 0 Participants | 8 Participants | 11 Participants |
| Childbearing Potential Not Applicable | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 6 Participants |
| Childbearing Potential Yes | 0 Participants | 4 Participants | 1 Participants | 6 Participants | 11 Participants |
| Height (cm) >1.65 | 1 Participants | 5 Participants | 2 Participants | 7 Participants | 15 Participants |
| Height (cm) <=1.65cm | 0 Participants | 1 Participants | 0 Participants | 12 Participants | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 6 Participants | 2 Participants | 19 Participants | 28 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 1 Participants | 14 Participants | 21 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 5 Participants | 7 Participants |
| Weight (kg) <71,5kg | 0 Participants | 3 Participants | 1 Participants | 16 Participants | 20 Participants |
| Weight (kg) >71,5kg | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 28 | 0 / 27 | 0 / 21 |
| other Total, other adverse events | 10 / 29 | 15 / 28 | 15 / 27 | 11 / 21 |
| serious Total, serious adverse events | 0 / 29 | 2 / 28 | 0 / 27 | 0 / 21 |
Outcome results
Primary
Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg
This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat
Time frame: Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after investigational medicinal product (IMP) intake)
Population: Following multiple administrations of the HTD of zamicastat to pulmonary arterial hypertension (PAH) patients at maintenance period visit (MPV)3, pharmacokinetic (PK) concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | Zamicastat | 155 ng.h/mL | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-453_2 | 181 ng.h/mL | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-453_1 | 172 ng.h/mL | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-961 | 150,187 ng.h/mL | Standard Deviation 0 |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | Zamicastat | 761 ng.h/mL | Standard Deviation 44.6 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-961 | 277 ng.h/mL | Standard Deviation 94.3 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | Zamicastat | 1570 ng.h/mL | Standard Deviation 59.7 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-453_1 | 305 ng.h/mL | Standard Deviation 38.5 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL) - 50 mg | BIA 5-453_2 | 305 ng.h/mL | Standard Deviation 38.5 |
Primary
Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD
This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD)
Time frame: 1, 2, 4, 8, 16 and 24 hours after IMP intake
Population: Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | Zamicastat | 3.09 ng.h/mL/mg | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | Zamicastat | 7.61 ng.h/mL/mg | Standard Deviation 44.6 |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-453_1 | 1.72 ng.h/mL/mg | Standard Deviation 0 |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-453_2 | 1.81 ng.h/mL/mg | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-961_1 | 1.50 ng.h/mL/mg | — |
| 100 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-961_2 | 1.87 ng.h/mL/mg | — |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-453_2 | 1.53 ng.h/mL/mg | Standard Deviation 38.5 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-961_2 | 1.39 ng.h/mL/mg | Standard Deviation 94.3 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-961_1 | 1.39 ng.h/mL/mg | Standard Deviation 94.3 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | BIA 5-453_1 | 1.53 ng.h/mL/mg | Standard Deviation 38.5 |
| 200 mg Zamicastat Once Daily | Area Under the Curve 0-24h (AUC0-24h) (ng.h/mL/mg) - HTD | Zamicastat | 7.87 ng.h/mL/mg | Standard Deviation 59.7 |
Primary
Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg
This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat
Time frame: Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake)
Population: Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | Zamicastat | 13.3 ng/mL | — |
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_1 | 5.39 ng/mL | — |
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_2 | 5.39 ng/mL | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_2 | 23.9 ng/mL | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_1 | 11.0 ng/mL | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | Zamicastat | 62.6 ng/mL | Standard Deviation 60.5 |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | 5-453 | 8.39 ng/mL | Standard Deviation 33.1 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | Zamicastat | 134 ng/mL | Standard Deviation 94 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | 5-453 | 18.8 ng/mL | Standard Deviation 48.1 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_1 | 17.6 ng/mL | Standard Deviation 78.2 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL) - 50 mg | BIA 5-961_2 | 17.6 ng/mL | Standard Deviation 78.2 |
Primary
Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD
This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD)
Time frame: 1, 2, 4, 8, 16 and 24 hours after IMP intake
Population: Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | Zamicastat | 0.27 ng/mL/mg | — |
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_1 | 0.108 ng/mL/mg | — |
| 50 mg Zamicastat | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_2 | 0.108 ng/mL/mg | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_2 | 0.239 ng/mL/mg | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_1 | 0.110 ng/mL/mg | — |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | Zamicastat | 0.626 ng/mL/mg | Standard Deviation 60.5 |
| 100 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-453 | 0.0839 ng/mL/mg | Standard Deviation 33.1 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | Zamicastat | 0.672 ng/mL/mg | Standard Deviation 94 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-453 | 0.0939 ng/mL/mg | Standard Deviation 48.1 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_1 | 0.0882 ng/mL/mg | Standard Deviation 78.2 |
| 200 mg Zamicastat Once Daily | Maximum Plasma Concentration (Cmax) (ng/mL/mg) - HTD | BIA 5-961_2 | 0.0882 ng/mL/mg | Standard Deviation 78.2 |
Primary
Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD
This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD). Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
Time frame: 1, 2, 4, 8, 16 and 24 hours after IMP intake
Population: Non-numerical values reported in the plasma concentration data (i.e. values that are below the limit of quantification), will be treated as missing for the determination of summary statistics. This also applies to any concentrations that are defined as PK parameters (e.g. Cmin). Where less than 3 patients receive the same dose at MPV3 or there are less than 3 quantifiable concentrations at a time point or parameter, summary statistics will not be produced for this dose/visits or time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 100 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | Zamicastat | 0.186 ng/mL/mg | Standard Deviation 36.7 |
| 100 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-453_1 | 0.0564 ng/mL/mg | — |
| 100 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-453_2 | 0.0603 ng/mL/mg | — |
| 100 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-961 | 0.0896 ng/mL/mg | — |
| 200 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-961 | 0.0503 ng/mL/mg | Standard Deviation 58.6 |
| 200 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | Zamicastat | 0.198 ng/mL/mg | Standard Deviation 74.1 |
| 200 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-453_2 | 0.0479 ng/mL/mg | Standard Deviation 48.5 |
| 200 mg Zamicastat Once Daily | Minimum Plasma Concentration at the End of the Dosing Interval (Cmin,SS) (ng/mL/mg) - HTD | BIA 5-453_1 | 0.0479 ng/mL/mg | Standard Deviation 48.5 |
Primary
Time Until Cmax (Tmax) (h) - 50 mg
This PK parameters (24-hour profile) for zamicastat and its metabolites will be derived after a single dose of 50 mg zamicastat
Time frame: Day 1 (0 hours and then 1, 2, 4, 8, 16 and 24 hours after IMP intake)
Population: Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Time Until Cmax (Tmax) (h) - 50 mg | BIA 5-961 | 4.03 h | — |
| 50 mg Zamicastat | Time Until Cmax (Tmax) (h) - 50 mg | Zamicastat | 2.00 h | — |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | BIA 5-961 | 2.00 h | — |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | BIA 5-453 | 3.00 h | Standard Deviation 2 |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | Zamicastat | 3.00 h | Standard Deviation 1 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | BIA 5-961 | 8.00 h | Standard Deviation 4 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | Zamicastat | 4.00 h | Standard Deviation 1 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - 50 mg | BIA 5-453 | 4.05 h | Standard Deviation 2 |
Primary
Time Until Cmax (Tmax) (h) - HTD
This PK parameter (24-hour profile) for zamicastat and its metabolites will be derived at steady-state at the individual highest tolerated dose (HTD)
Time frame: 1, 2, 4, 8, 16 and 24 hours after IMP intake
Population: Following multiple administrations of the HTD of zamicastat to PAH patients at MPV3, PK concentrations and parameter summaries for only the 50 mg, 100 mg and 200 mg dose levels are presented and discussed, as the only subject receiving the 150 mg HTD level had a major protocol deviation documented, impacting the reliability of their PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 50 mg Zamicastat | Time Until Cmax (Tmax) (h) - HTD | BIA 5-961 | 4.03 h | — |
| 50 mg Zamicastat | Time Until Cmax (Tmax) (h) - HTD | Zamicastat | 2.00 h | — |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | BIA 5-961 | 8.08 h | — |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | BIA 5-453 | 3.00 h | Standard Deviation 8.08 |
| 100 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | Zamicastat | 3.00 h | Standard Deviation 4.08 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | BIA 5-961 | 8.00 h | Standard Deviation 24 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | Zamicastat | 4.00 h | Standard Deviation 24 |
| 200 mg Zamicastat Once Daily | Time Until Cmax (Tmax) (h) - HTD | BIA 5-453 | 4.05 h | Standard Deviation 24 |