Tuberculosis
Conditions
Keywords
Tuberculosis
Brief summary
Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in fasted healthy volunteers after single and multiple oral administration
Detailed description
Open-label prospective non-comparative safety, tolerability and pharmacokinetics ascending dose randomized cohort study of PBTZ169 (capsules 40 mg) in adult man healthy volunteers after single and multiple oral fasting administration. Study was conducted in one study center in Russian Federation. The study included two stages: * Stage 1 - single oral fasting administration with dose escalation in 5 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group); * Stage 2 - multiple oral fasting administration with dose escalation in 2 cohorts 6 healthy man volunteers each in main groups (plus 1 back-up volunteer in every group). Screening procedures for each cohort performed within 7 days before the drug prescription and after the end of administration period in previous cohort. Screening in cohorts 2 and 6 was started only after safety tolerability and PK data analysis of previous cohorts. All volunteers met the study inclusion/exclusion criteria was included successively into the following cohorts on Stage 1 (actual data): * Cohort 1 (C1) - 6 volunteers of the main group each of whom received once single dose of the drug - 1 capsule containing 40 mg of PBTZ169; * Cohort 2 (C2) - 6 volunteers of the main group each of whom received once 80 mg of PBTZ169 (2 capsules 40 mg); * Cohort 3 (C3) - 6 volunteers of the main group each of whom received once 160 mg of PBTZ169 (4 capsules 40 mg); * Cohort 4 (C4) - 6 volunteers of the main group each of whom received once 320 mg of PBTZ169 (8 capsules 40 mg); * Cohort 5 (C5) - 6 volunteers of the main group each of whom received once 640 mg of PBTZ169 (16 capsules 40 mg). On Stage 2 (actual data): * Cohort 6 (C6) - 5 volunteers of the main group each of whom received 320 mg of PBTZ169 (8 capsules 40 mg) once daily for 14 days; * Cohort 7 (C7) - 5 volunteers of the main group each of whom received 640 mg of PBTZ169 (16 capsules 40 mg) once daily for 14 days. Safety was assessed throughout the study. For every volunteer series of urine and venous blood samples was collected for the safety, tolerability and PK assessment of PBTZ169.
Interventions
DRUGPBTZ169 - 40 mg
40 mg of PBTZ169 (1 capsule) orally once in fasting state
DRUGPBTZ169 - 80 mg
80 mg of PBTZ169 (2 capsules 40 mg) orally once in fasting state
DRUGPBTZ169 - 160 mg
160 mg of PBTZ169 (4 capsules 40 mg) orally once in fasting state
DRUGPBTZ169 - 320 mg
320 mg of PBTZ169 (8 capsules 40 mg) orally once in fasting state
DRUGPBTZ169 - 640 mg
640 mg of PBTZ169 (16 capsules 40 mg) orally once in fasting state
DRUGPBTZ169 - 320 mg (multiple administration)
320 mg of PBTZ169 (8 capsules 40 mg) orally once per day in fasting state for 14 days
DRUGPBTZ169 - 640 mg (multiple administration)
640 mg of PBTZ169 (16 capsules 40 mg) orally once per day in fasting state for 14 days
Sponsors
OCT LLC
Nearmedic Plus LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Written informed consent received from a volunteer. 2. Man aged 18 to 45 years old, inclusive. 3. Body mass index of 18.5-25 kg/m2. 4. Verified diagnosis: healthy according to data of standard clinical, laboratory and instrumental examination methods performed at screening: * Absence of deviations of physical examination parameters and vital signs (systolic blood pressure - 100-129 mm Hg, inclusive; diastolic blood pressure - 70-89 mm Hg, inclusive; heart rate - 60-80 bpm, inclusive); * Absence of deviations of laboratory parameters (complete blood count, blood biochemistry, urinalysis and tests for HIV, HBV, HCV, syphilis); * Normal parameters of 12-lead ECG; * Normal results of photofluorographic or X-ray examination (the results received maximum 6 months before screening can be used). 5. Ability, according to investigators opinion, to comply with all requirements of the protocol. 6. Agreement to use double contraception method during the study participation and for 3 months after the test drug administration - combination of male condom with not less than one of the following methods: * female partner using hormonal contraception; * using aerosols, creams, suppositories and other agents containing spermicides; * female partner using intrauterine device
Exclusion criteria
1. Aggravated allergic history, including presence of at least one episode of drug allergy. 2. Chronic diseases of cardiovascular, bronchopulmonary, neuroendocrine systems, ENT and gastrointestinal, hepatic, renal, blood and cutaneous diseases. 3. Chronic diseases of eyes except for mild to moderate myopia, hypermetropia and astigmatism. 4. Gastrointestinal surgeries (except for appendectomy performed not less than 1 year before screening). 5. Acute infections within less than 4 weeks before screening. 6. Regular drug administration within less than 4 weeks before screening. 7. Regular administration or application (including topical) of hormonal drugs for more than 1 week within less than 45 days before the screening. 8. Administration of drugs exerting evident effects on hemodynamics, hepatic function, etc. (barbiturates, omeprazole, cimetidine, etc.) within less than 45 days before the screening. 9. Positive tests for narcotic and psychotropic agents. 10. Donation (450 mL of blood or plasma) within less than 3 months before the screening. 11. Intake of more than 10 U of alcohol per week (1 unit of alcohol is equivalent to 500 mL of beer, 200 mL of vine or 50 mL of strong alcoholic drink) or historical data on alcoholism, narcomania, drug abuse. 12. Mental illnesses. 13. Smoking within half a year before the screening. 14. Previous participation in this clinical study and withdrawal from it due to any reason. 15. Participation in other clinical studies of drugs within less than 6 months before the screening. 16. Planned conception or sperm donation during the study after the test drug administration or during 3 months after the date of drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Drug-related Adverse Events [Safety and Tolerability] | 14±1 days after the drug administration (up to last visit time point) | The frequency of adverse events for which a relationship to the test drug PBTZ169 was noted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Up to 72 hours after the last drug administration | Single dosing (Cohorts 1-5): data for the dosing day (Day 1). Multiple dosing (Cohorts 6, 7): data for days 1 (1st dose), 7 and 14 (last dose) |
| Area Under the Concentration-time Curve (AUC0-∞) | Up to 72 hours after the last drug administration | In the time interval from 0 to infinity |
| Plasma Half-life Time (T1/2) of PBTZ169 | Up to 72 hours after the last drug administration | Single dosing (Cohorts 1-5): data for the dosing day (Day 1). Multiple dosing (Cohorts 6, 7): data for days 1 (1st dose), 7 and 14 (last dose) |
| Mean Plasma Retention Time (MRT) of PBTZ169 | Up to 72 hours after the last drug administration | — |
| Total (Plasma) Clearance (Cl) of PBTZ169 | Up to 72 hours after the last drug administration | The Cl parameter was calculated using the following formulas: for Day 1: Cl=D/AUCinf; for Days 7 and 14: Clss=D/AUCτ |
| Volume of Distribution (Vd) of PBTZ169 | Up to 72 hours after the last drug administration | — |
| Elimination Constant (Kel) of PBTZ169 | Up to 72 hours after the last drug administration | Data for doses 320 mg (Cohorts 4 and 6, total 11 volunters) & 640 mg (Cohorts 5 and 7, total 11 volunters) were combined |
| Peak Plasma Concentration (Сmax) of PBTZ169 | Up to 72 hours after the last drug administration | Up to 72 hours after the last drug administration: Single dosing (Cohorts 1-5): up to Day 4 (72 h after the dosing (Day 1)) Multiple dosing (Cohorts 6. 7): up to Day 17 (72 h after the last (14th) dosing) |
| Peak Steady State Plasma Concentration (Cmax,ss) of PBTZ169 | Up to 72 hours after the last drug administration | For cohorts 6 and 7 (multiple administration) only |
| Time to Reach Maximum Steady State Concentration (Tmax,ss) of PBTZ169 | Up to 72 hours after the last drug administration | For cohorts 6 and 7 (multiple administration) only |
| Area Under the Plasma Concentration Versus Time Curve in Steady State (AUCss) of PBTZ169 | Up to 72 hours after the last drug administration | For cohorts 6 and 7 (multiple administration) only |
| Volume of Steady State Distribution (Vd,ss) of PBTZ169 | Up to 72 hours after the last drug administration | For cohorts 6 and 7 (multiple administration) only |
| Area Under the Concentration-time Curve (AUC0-t) | Up to 72 hours after the last drug administration | The area under the concentration-time curve from 0 to last blood sampling |
| AUC0-t/AUC0-∞ | Up to 72 hours after the last drug administration | AUC0-t/AUC0-∞ ratio |
| Renal Clearance (Clren) of PBTZ169 | Up to 24 hours after the drug administration | The renal clearance was calculated using values of the cumulative excretion in urine (from zero to 24 hours) and the area under the pharmacokinetic curve (from zero to 24 hours) (the ratio of the cumulative excretion to AUC0-24) |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 6 healthy volunteers each of whom received one single oral dose of PBTZ169 - 40 mg (1 capsule)
PBTZ169 - 40 mg: 40 mg of PBTZ169 (1 capsule) orally once in fasting state | 6 |
| Cohort 2 6 healthy volunteers each of whom received one single oral dose of PBTZ169 - 80 mg (2 capsules)
PBTZ169 - 80 mg: 80 mg of PBTZ169 (2 capsules 40 mg) orally once in fasting state | 6 |
| Cohort 3 6 healthy volunteers each of whom received one single oral dose of PBTZ169 - 160 mg (4 capsules)
PBTZ169 - 160 mg: 160 mg of PBTZ169 (4 capsules 40 mg) orally once in fasting state | 6 |
| Cohort 4 6 healthy volunteers each of whom received one single oral dose of PBTZ169 - 320 mg (8 capsules)
PBTZ169 - 320 mg: 320 mg of PBTZ169 (8 capsules 40 mg) orally once in fasting state | 6 |
| Cohort 5 6 healthy volunteers each of whom received one single oral dose of PBTZ169 - 640 mg (16 capsules)
PBTZ169 - 640 mg: 640 mg of PBTZ169 (16 capsules 40 mg) orally once in fasting state | 6 |
| Cohort 6 5 healthy volunteers each of whom received а daily dose of 320 mg of PBTZ169 (8 capsules 40 mg) for 14 days
PBTZ169 - 320 mg (multiple administration): 320 mg of PBTZ169 (8 capsules 40 mg) orally once per day in fasting state for 14 days | 5 |
| Cohort 7 5 healthy volunteers each of whom received a daily dose of 640 mg of PBTZ169 (16 capsules 40 mg) for 14 days
PBTZ169 - 640 mg (multiple administration): 640 mg of PBTZ169 (16 capsules 40 mg) orally once per day in fasting state for 14 days | 5 |
| Total | 40 |
Baseline characteristics
| Characteristic | Cohort 1 | Total | Cohort 7 | Cohort 6 | Cohort 5 | Cohort 4 | Cohort 3 | Cohort 2 |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.8 years STANDARD_DEVIATION 5 | 27.6 years STANDARD_DEVIATION 5.85 | 28.6 years STANDARD_DEVIATION 6.5 | 22.6 years STANDARD_DEVIATION 2.61 | 29.0 years STANDARD_DEVIATION 7.18 | 31.2 years STANDARD_DEVIATION 6.85 | 31.8 years STANDARD_DEVIATION 6.55 | 27.8 years STANDARD_DEVIATION 5.64 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 40 Participants | 5 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
| Region of Enrollment Russia | 6 participants | 40 participants | 5 participants | 5 participants | 6 participants | 6 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 40 Participants | 5 Participants | 5 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 2 / 6 | 2 / 6 | 1 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 1 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 5 |
Outcome results
Primary
Incidence of Drug-related Adverse Events [Safety and Tolerability]
The frequency of adverse events for which a relationship to the test drug PBTZ169 was noted
Time frame: 14±1 days after the drug administration (up to last visit time point)
Population: Safety population: subjects who received at least one dose of PBTZ169. The population was used for the analysis and evaluation of the demographic and other baseline data and all safety parameters including AEs, physical examination, evaluation of the vital signs, previous and current therapy, ECG, all laboratory tests
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 2 participants |
| Cohort 2 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 2 participants |
| Cohort 3 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 1 participants |
| Cohort 4 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 0 participants |
| Cohort 5 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 0 participants |
| Cohort 6 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 1 participants |
| Cohort 7 | Incidence of Drug-related Adverse Events [Safety and Tolerability] | 1 participants |
Secondary
Area Under the Concentration-time Curve (AUC0-∞)
In the time interval from 0 to infinity
Time frame: Up to 72 hours after the last drug administration
Population: PKA: C1-5 - SAD, C6-7 - MAD for 14 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 349.25 ng*h/ml | Standard Deviation 206.53 |
| Cohort 2 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 452.83 ng*h/ml | Standard Deviation 148.58 |
| Cohort 3 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 1096.36 ng*h/ml | Standard Deviation 543.62 |
| Cohort 4 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 1329.65 ng*h/ml | Standard Deviation 250.95 |
| Cohort 5 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 3028.04 ng*h/ml | Standard Deviation 1286.88 |
| Cohort 6 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 1450.21 ng*h/ml | Standard Deviation 586.73 |
| Cohort 6 | Area Under the Concentration-time Curve (AUC0-∞) | Day 7 | 2747.33 ng*h/ml | Standard Deviation 795.07 |
| Cohort 6 | Area Under the Concentration-time Curve (AUC0-∞) | Day 14 | 3410.12 ng*h/ml | Standard Deviation 1204.07 |
| Cohort 7 | Area Under the Concentration-time Curve (AUC0-∞) | Day 7 | 3024.29 ng*h/ml | Standard Deviation 726.15 |
| Cohort 7 | Area Under the Concentration-time Curve (AUC0-∞) | Dosing day / Day 1 | 1696.28 ng*h/ml | Standard Deviation 993.13 |
| Cohort 7 | Area Under the Concentration-time Curve (AUC0-∞) | Day 14 | 4358.90 ng*h/ml | Standard Deviation 649.33 |
Secondary
Area Under the Concentration-time Curve (AUC0-t)
The area under the concentration-time curve from 0 to last blood sampling
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Area Under the Concentration-time Curve (AUC0-t) | 260.47 ng*h/ml | Standard Deviation 119.06 |
| Cohort 2 | Area Under the Concentration-time Curve (AUC0-t) | 381.17 ng*h/ml | Standard Deviation 149.39 |
| Cohort 3 | Area Under the Concentration-time Curve (AUC0-t) | 994.49 ng*h/ml | Standard Deviation 462 |
| Cohort 4 | Area Under the Concentration-time Curve (AUC0-t) | 1193.70 ng*h/ml | Standard Deviation 212.53 |
| Cohort 5 | Area Under the Concentration-time Curve (AUC0-t) | 2880.86 ng*h/ml | Standard Deviation 1219.3 |
Secondary
Area Under the Plasma Concentration Versus Time Curve in Steady State (AUCss) of PBTZ169
For cohorts 6 and 7 (multiple administration) only
Time frame: Up to 72 hours after the last drug administration
Secondary
AUC0-t/AUC0-∞
AUC0-t/AUC0-∞ ratio
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | AUC0-t/AUC0-∞ | 0.784 ratio |
| Cohort 2 | AUC0-t/AUC0-∞ | 0.829 ratio |
| Cohort 3 | AUC0-t/AUC0-∞ | 0.917 ratio |
| Cohort 4 | AUC0-t/AUC0-∞ | 0.899 ratio |
| Cohort 5 | AUC0-t/AUC0-∞ | 0.951 ratio |
Secondary
Elimination Constant (Kel) of PBTZ169
Data for doses 320 mg (Cohorts 4 and 6, total 11 volunters) & 640 mg (Cohorts 5 and 7, total 11 volunters) were combined
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Elimination Constant (Kel) of PBTZ169 | 0.052 1/h | Standard Deviation 0.01329 |
| Cohort 2 | Elimination Constant (Kel) of PBTZ169 | 0.077 1/h | Standard Deviation 0.0266 |
| Cohort 3 | Elimination Constant (Kel) of PBTZ169 | 0.063 1/h | Standard Deviation 0.0082 |
| Cohort 4 | Elimination Constant (Kel) of PBTZ169 | 0.066 1/h | Standard Deviation 0.0212 |
| Cohort 5 | Elimination Constant (Kel) of PBTZ169 | 0.066 1/h | Standard Deviation 0.0151 |
| Cohort 6 | Elimination Constant (Kel) of PBTZ169 | 0.066 1/h | Standard Deviation 0.0212 |
| Cohort 7 | Elimination Constant (Kel) of PBTZ169 | 0.066 1/h | Standard Deviation 0.0151 |
Secondary
Mean Plasma Retention Time (MRT) of PBTZ169
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 15.70 h | Standard Deviation 6.12 |
| Cohort 2 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 13.02 h | Standard Deviation 4.26 |
| Cohort 3 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 15.44 h | Standard Deviation 3.88 |
| Cohort 4 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 17.38 h | Standard Deviation 3.68 |
| Cohort 5 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 19.30 h | Standard Deviation 4.16 |
| Cohort 6 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 7.65 h | Standard Deviation 0.61 |
| Cohort 6 | Mean Plasma Retention Time (MRT) of PBTZ169 | Day 7 | 8.35 h | Standard Deviation 0.75 |
| Cohort 6 | Mean Plasma Retention Time (MRT) of PBTZ169 | Day 14 | 16.78 h | Standard Deviation 1.71 |
| Cohort 7 | Mean Plasma Retention Time (MRT) of PBTZ169 | Day 7 | 8.45 h | Standard Deviation 0.8 |
| Cohort 7 | Mean Plasma Retention Time (MRT) of PBTZ169 | Dosing day / Day 1 | 7.70 h | Standard Deviation 0.43 |
| Cohort 7 | Mean Plasma Retention Time (MRT) of PBTZ169 | Day 14 | 17.89 h | Standard Deviation 2.25 |
Secondary
Peak Plasma Concentration (Сmax) of PBTZ169
Up to 72 hours after the last drug administration: Single dosing (Cohorts 1-5): up to Day 4 (72 h after the dosing (Day 1)) Multiple dosing (Cohorts 6. 7): up to Day 17 (72 h after the last (14th) dosing)
Time frame: Up to 72 hours after the last drug administration
Population: Pharmacokinetics analysis population (PKA): C1-5: sbjs who received PBTZ169 and had at least one measurement of PBTZ169 concentration; C6-7: sbjs who received PBTZ169 at least 7 times and had measurements of PBTZ169 concentration after the first and seventh administration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 40.67 ng/ml | Standard Deviation 15.28 |
| Cohort 2 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 66.99 ng/ml | Standard Deviation 33.81 |
| Cohort 3 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 135.85 ng/ml | Standard Deviation 46.32 |
| Cohort 4 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 156.25 ng/ml | Standard Deviation 65.54 |
| Cohort 5 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 349.67 ng/ml | Standard Deviation 145.92 |
| Cohort 6 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 190.82 ng/ml | Standard Deviation 37.51 |
| Cohort 6 | Peak Plasma Concentration (Сmax) of PBTZ169 | Day 7 | 243.22 ng/ml | Standard Deviation 59.51 |
| Cohort 6 | Peak Plasma Concentration (Сmax) of PBTZ169 | Day 14 | 300.55 ng/ml | Standard Deviation 82.24 |
| Cohort 7 | Peak Plasma Concentration (Сmax) of PBTZ169 | Day 7 | 278.64 ng/ml | Standard Deviation 70.68 |
| Cohort 7 | Peak Plasma Concentration (Сmax) of PBTZ169 | Day 14 | 453.73 ng/ml | Standard Deviation 111.85 |
| Cohort 7 | Peak Plasma Concentration (Сmax) of PBTZ169 | Dosing day / Day 1 | 250.54 ng/ml | Standard Deviation 144.33 |
Secondary
Peak Steady State Plasma Concentration (Cmax,ss) of PBTZ169
For cohorts 6 and 7 (multiple administration) only
Time frame: Up to 72 hours after the last drug administration
Secondary
Plasma Half-life Time (T1/2) of PBTZ169
Single dosing (Cohorts 1-5): data for the dosing day (Day 1). Multiple dosing (Cohorts 6, 7): data for days 1 (1st dose), 7 and 14 (last dose)
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 14.306 h | Standard Deviation 4.516 |
| Cohort 2 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 10.182 h | Standard Deviation 3.663 |
| Cohort 3 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 16.147 h | Standard Deviation 3.461 |
| Cohort 4 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 16.447 h | Standard Deviation 2.947 |
| Cohort 5 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 18.175 h | Standard Deviation 3.824 |
| Cohort 6 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 12.40 h | Standard Deviation 5.72 |
| Cohort 6 | Plasma Half-life Time (T1/2) of PBTZ169 | Day 7 | 12.62 h | Standard Deviation 5.02 |
| Cohort 6 | Plasma Half-life Time (T1/2) of PBTZ169 | Day 14 | 17.16 h | Standard Deviation 4.35 |
| Cohort 7 | Plasma Half-life Time (T1/2) of PBTZ169 | Day 7 | 14.16 h | Standard Deviation 1.92 |
| Cohort 7 | Plasma Half-life Time (T1/2) of PBTZ169 | Dosing day / Day 1 | 9.98 h | Standard Deviation 2.2 |
| Cohort 7 | Plasma Half-life Time (T1/2) of PBTZ169 | Day 14 | 17.95 h | Standard Deviation 2.5 |
Secondary
Renal Clearance (Clren) of PBTZ169
The renal clearance was calculated using values of the cumulative excretion in urine (from zero to 24 hours) and the area under the pharmacokinetic curve (from zero to 24 hours) (the ratio of the cumulative excretion to AUC0-24)
Time frame: Up to 24 hours after the drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 12.12 mL/h | Standard Deviation 7.62 |
| Cohort 2 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 12.64 mL/h | Standard Deviation 7.72 |
| Cohort 3 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 7.16 mL/h | Standard Deviation 3.8 |
| Cohort 4 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 11.81 mL/h | Standard Deviation 1.22 |
| Cohort 5 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 17.72 mL/h | Standard Deviation 6.37 |
| Cohort 6 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 8.5 mL/h | Standard Deviation 5.8 |
| Cohort 6 | Renal Clearance (Clren) of PBTZ169 | Day 14 | 5.7 mL/h | Standard Deviation 3.3 |
| Cohort 7 | Renal Clearance (Clren) of PBTZ169 | Dosing day / Day 1 | 11.2 mL/h | Standard Deviation 2.9 |
| Cohort 7 | Renal Clearance (Clren) of PBTZ169 | Day 14 | 7.6 mL/h | Standard Deviation 3.2 |
Secondary
Time to Reach Maximum Concentration (Tmax) of PBTZ169
Single dosing (Cohorts 1-5): data for the dosing day (Day 1). Multiple dosing (Cohorts 6, 7): data for days 1 (1st dose), 7 and 14 (last dose)
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 2.50 h |
| Cohort 2 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 1.50 h |
| Cohort 3 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 2.00 h |
| Cohort 4 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 2.50 h |
| Cohort 5 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 1.50 h |
| Cohort 6 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 1.50 h |
| Cohort 6 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Day 7 | 2.00 h |
| Cohort 6 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Day 14 | 2.00 h |
| Cohort 7 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Day 7 | 2.00 h |
| Cohort 7 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Dosing day / Day 1 | 1.50 h |
| Cohort 7 | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | Day 14 | 2.00 h |
Secondary
Time to Reach Maximum Steady State Concentration (Tmax,ss) of PBTZ169
For cohorts 6 and 7 (multiple administration) only
Time frame: Up to 72 hours after the last drug administration
Secondary
Total (Plasma) Clearance (Cl) of PBTZ169
The Cl parameter was calculated using the following formulas: for Day 1: Cl=D/AUCinf; for Days 7 and 14: Clss=D/AUCτ
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 147.35 L/h | Standard Deviation 71.97 |
| Cohort 2 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 190.75 L/h | Standard Deviation 52.79 |
| Cohort 3 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 173.96 L/h | Standard Deviation 69.47 |
| Cohort 4 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 248.08 L/h | Standard Deviation 47.99 |
| Cohort 5 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 240.40 L/h | Standard Deviation 89.12 |
| Cohort 6 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 244.15 L/h | Standard Deviation 74.982 |
| Cohort 6 | Total (Plasma) Clearance (Cl) of PBTZ169 | Day 7 | 197.223 L/h | Standard Deviation 45.706 |
| Cohort 6 | Total (Plasma) Clearance (Cl) of PBTZ169 | Day 14 | 146.44 L/h | Standard Deviation 45.573 |
| Cohort 7 | Total (Plasma) Clearance (Cl) of PBTZ169 | Day 7 | 310.74 L/h | Standard Deviation 76.273 |
| Cohort 7 | Total (Plasma) Clearance (Cl) of PBTZ169 | Dosing day / Day 1 | 462.83 L/h | Standard Deviation 197.223 |
| Cohort 7 | Total (Plasma) Clearance (Cl) of PBTZ169 | Day 14 | 224.79 L/h | Standard Deviation 42.994 |
Secondary
Volume of Distribution (Vd) of PBTZ169
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 2762.47 L | Standard Deviation 1052.08 |
| Cohort 2 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 2949.95 L | Standard Deviation 1652.24 |
| Cohort 3 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 3903.25 L | Standard Deviation 1354.34 |
| Cohort 4 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 5801.14 L | Standard Deviation 1006.47 |
| Cohort 5 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 6359.85 L | Standard Deviation 2861.493 |
| Cohort 6 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 3924.74 L | Standard Deviation 401.074 |
| Cohort 6 | Volume of Distribution (Vd) of PBTZ169 | Day 7 | 2957.51 L | Standard Deviation 1671.483 |
| Cohort 6 | Volume of Distribution (Vd) of PBTZ169 | Day 14 | 3392.46 L | Standard Deviation 2005.822 |
| Cohort 7 | Volume of Distribution (Vd) of PBTZ169 | Day 7 | 6114.55 L | Standard Deviation 1680.928 |
| Cohort 7 | Volume of Distribution (Vd) of PBTZ169 | Dosing day / Day 1 | 6521.98 L | Standard Deviation 2719.519 |
| Cohort 7 | Volume of Distribution (Vd) of PBTZ169 | Day 14 | 4067.27 L | Standard Deviation 2374.585 |
Secondary
Volume of Steady State Distribution (Vd,ss) of PBTZ169
For cohorts 6 and 7 (multiple administration) only
Time frame: Up to 72 hours after the last drug administration