Tuberculosis
Conditions
Keywords
Tuberculosis, PBTZ169, antimycobacterial
Brief summary
Multicenter, open, randomized study with active control (isoniazid) to evaluate the early antibacterial activity, safety and pharmacokinetics of the drug PBTZ169 (capsules 80 mg) when used in patients with first-diagnosed tuberculosis of the respiratory system with bacterial excretion and saved bacterial susceptibility to isoniazid and rifampicin
Detailed description
This phase 2a study is aimed to evaluate the early bactericidal activity of a new anti-tuberculosis drug PBTZ169 (capsules 80 mg), and its results will allow preliminary evaluate antimycobacterial properties of PBTZ169 and confirm a potentially more effective dose for subsequent studies. This study is an open, randomized comparative efficacy (on the parameter of early bactericidal activity), safety and pharmacokinetics study of PBTZ169 in patients with first-diagnosed lung tuberculosis and preserved sensitivity to base antimycobacterial drugs: rifampicin and isoniazid. Within the framework of the study, it is planned to use the studied drugs (PBTZ169 and isoniazid) as monotherapy within 14 days. Isoniazid is used as a positive control, that is, in order to determine whether the method of assessing efficacy on the parameter of early bactericidal activity is working.
Interventions
DRUGPBTZ169
Once a day for 14 days
DRUGIsoniazid
Once a day for 14 days
Sponsors
OCT LLC
Nearmedic Plus LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Written informed consent received from a volunteer * Men and women aged 18 to 65 years, inclusive * The first-diagnosed active pulmonary tuberculosis, confirmed by characteristic radiographic changes (infiltration, dissemination, destruction) during radiography or computed tomography of chest organs, without damage to other organs or with the defeat of one or more of the following organs: larynx, trachea, bronchi, lymph nodes * The amount of sputum given by the patient is sufficient for carrying out the analyzes provided for by the protocol, but not less than 4-5 ml at the screening * The presence of acid-fast mycobacteria in the sputum according to the results of microscopy of smears (1+ and more using the method of microscopy with luminescent dye staining according to the Order of the Ministry of Health of the Russian Federation of March 21, 2003 No. 109, the last edition) and the detection of the DNA of mycobacteria of tuberculosis by the results of molecular genetic methods of diagnosis * Body weight not less than 51 kg * Body mass index of 18.5-25 kg/m2 * Ability, according to investigators opinion, to comply with all requirements of the protocol * 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
* Extrapulmonary localization of tuberculosis * Presence of resistance to rifampicin and / or isoniazid in the study of sputum samples using molecular genetic methods * Admission of any anti-tuberculosis drugs from the moment of diagnosis of tuberculosis to the moment of inclusion in the study * The presence of absolute indications for surgical treatment of tuberculosis at the time of screening * Positive tests for serological markers of syphilis or HIV infection during screening; active hepatitis or decompensated hepatic cirrhosis * Aggravated allergic history, including presence of at least one episode of drug allergy * The values of renal and / or hepatic parameters according to laboratory analyzes (taking into account the range of normal laboratory values): * Aspartate aminotransferase (AST) level \> 2.0 x upper limit of the norm * Alanine aminotransferase (ALT) level \> 2.0 x upper limit of norm * General bilirubin level \> 1.5 x upper limit of norm * Creatinine level \> 1.5 x upper limit of norm * Individual drug components intolerance * Presence in the anamnesis of malignant neoplasms, except for basal cell skin cancer * The presence of severe chronic somatic diseases in the stage of decompensation, including diseases of the cardiovascular, bronchopulmonary, neuroendocrine system, ear, nose and throat (ENT) organs, the gastrointestinal tract, liver, kidneys, blood, skin, or any other somatic or mental diseases that, according to the researcher, prevent the patient from entering the study * Gastrointestinal surgeries (except for appendectomy performed not less than 1 year before screening) * Mental illness that may interfere with the patient's compliance with the protocol * Diabetes mellitus * Acute viral and bacterial infections at the time of enrollment or within 2 weeks before enrollment * Alcoholism (except in cases when the patient is able, in the opinion of the researcher, to refrain from taking alcohol during the period of participation in the study), drug addiction, abuse of medicines * Positive tests for narcotic and psychotropic agents * Regular admission or use (including externally) of any hormonal medicines lasting more than 1 week less than 30 days before screening (with the exception of oral hormonal contraceptives and intrauterine spirals containing hormones) * Use of cytostatic drugs less than 30 days before screening * Multiple admission of drugs with the described in the instructions for medical use adverse events related to nervous system, hemodynamic and hepatic functions with frequencies very frequent (≥10%) and often (≥1% and \<10%) less than 21 days before screening * Pregnancy or lactation period * Planned conception or sperm donation during the study after the test drug administration or during 3 months after the last date of drug administration * Participation in other clinical studies of drugs within less than 3 months before the screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Bactericidal Activity (0-14) | 14 days after the onset of monotherapy | Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): agar inoculation, the mean of two measurements at the Visit |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Early Bactericidal Activity (0-7) | 7 days after the onset of monotherapy | EBA (0-7): agar inoculation, the mean of two measurements at the Visit |
| Peak Plasma Concentration (Сmax) of PBTZ169 | Up to 72 hours after the last drug administration | Peak plasma concentration (Сmax) of PBTZ169 for multiple dosing |
| Minimal Plasma Concentration (Сmin) of PBTZ169 | for single dosing , Day 1 (24 h after 1st dose of PBTZ169) | Minimal plasma concentration (Сmin) of PBTZ169: concentration measurement following single dosing |
| Residual Concentration (Ctrough) of PBTZ169 | Up to 72 hours after the last drug administration | Residual concentration (Ctrough) of PBTZ169, measured 24 hours after the first dose administration, prior to the last dose, and 24 hours after the last dose |
| Time to Reach Maximum Concentration (Tmax) of PBTZ169 | for single dosing , Day 1 (24 h after 1st dose of PBTZ169) | Time to reach maximum concentration (Tmax) of PBTZ169 after single oral administration in different doses |
| AUC(0-24) | Up to 24 hours after the first drug administration | Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-24 hours\] |
| AUC (0-t) | Up to 72 hours after the last drug administration | Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-last concentration above lower limit of quantification (LLoQ)\] |
| Early Bactericidal Activity (0-2) | 2 days after the onset of monotherapy | EBA (0-2): agar inoculation, the mean of two measurements at the Visit |
| Accumulation Ratios for the PK Parameters AUC(0 -24) | 24 hours after the first and the last drug administration | Accumulation ratios for the PK parameter AUC(0 -24): AUC(0- 24,ss)/AUC(0 -24), Day 1, on the original scale |
| Average Concentration (Css,av) of PBTZ169 | Up to 72 hours after the last drug administration | Average steady-state concentration in the dosing interval following multiple dosing was evaluated as the ratio AUC0 24/τ (τ = the dosing interval) |
| Fluctuations (%) in the Dosing Interval | Up to 72 hours after the last drug administration | Fluctuations (%) in the dosing interval after multiple dosing ((Cmax - Cmin) × 100%/Css,av) |
| Total (Plasma) Clearance (Clt) of PBTZ169 | 24 hours after the first drug administration | Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl\_t/F=D/AUC where D is the daily dose of the drug. |
| Volume of Distribution (Vd) of PBTZ169 | Up to 72 hours after the last drug administration | Distribution volume Vd for a dosing interval of 72 hours after the last dose |
| Plasma Half-life Time (T1/2) of PBTZ169 | 24 hours after the fist drug administration | — |
| Elimination Constant (Kel) of PBTZ169 | 24 hours after the first drug administration | Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve. |
| AUC(0-∞) of PBTZ169 | Up to 72 hours after the last drug administration | Area under the plasma concentration versus time curve in frames \[0-∞\] |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PBTZ169, 160 mg 2 capsules 80 mg of PBTZ169 once a day for 14 days
PBTZ169: Once a day for 14 days | 4 |
| PBTZ169, 320 mg 4 capsules 80 mg of PBTZ169 once a day for 14 days
PBTZ169: Once a day for 14 days | 4 |
| PBTZ169, 640 mg 8 capsules 80 mg of PBTZ169 once a day for 14 days
PBTZ169: Once a day for 14 days | 7 |
| Isoniazid, 600 mg 2 tablets 300 mg of Isoniazid once a day for 14 days
Isoniazid: Once a day for 14 days | 1 |
| Total | 16 |
Baseline characteristics
| Characteristic | PBTZ169, 160 mg | Total | Isoniazid, 600 mg | PBTZ169, 640 mg | PBTZ169, 320 mg |
|---|---|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 13 | 46.1 years STANDARD_DEVIATION 12.3 | 41.0 years STANDARD_DEVIATION 0 | 43.7 years STANDARD_DEVIATION 14.8 | 48.8 years STANDARD_DEVIATION 10.7 |
| 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 | 4 Participants | 16 Participants | 1 Participants | 7 Participants | 4 Participants |
| Region of Enrollment Russia | 4 participants | 16 participants | 1 participants | 7 participants | 4 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 14 Participants | 1 Participants | 5 Participants | 4 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 / 4 | 0 / 4 | 0 / 7 | 0 / 1 |
| other Total, other adverse events | 3 / 4 | 3 / 4 | 2 / 7 | 0 / 1 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 1 / 7 | 0 / 1 |
Outcome results
Primary
Early Bactericidal Activity (0-14)
Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): agar inoculation, the mean of two measurements at the Visit
Time frame: 14 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-14) | 0.061 CFU per 1 mL of sputum | Standard Deviation 0.085 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-14) | 0.015 CFU per 1 mL of sputum | Standard Deviation 0.025 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-14) | 0.071 CFU per 1 mL of sputum | Standard Deviation 0.126 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-14) | 0.237 CFU per 1 mL of sputum | Standard Deviation 0 |
Primary
Early Bactericidal Activity (0-14)
Early bactericidal activity 14 days from the monotherapy start date (EBA 0-14): PCR, the mean of two measurements at the Visit
Time frame: 14 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-14) | 0.038 cell count per 1 mL of sputum | Standard Deviation 0.081 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-14) | -0.014 cell count per 1 mL of sputum | Standard Deviation 0.048 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-14) | 0.097 cell count per 1 mL of sputum | Standard Deviation 0.136 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-14) | -0.099 cell count per 1 mL of sputum | Standard Deviation 0 |
Secondary
Accumulation Ratios for the PK Parameters AUC(0 -24)
Accumulation ratios for the PK parameter AUC(0 -24): AUC(0- 24,ss)/AUC(0 -24), Day 1, on the original scale
Time frame: 24 hours after the first and the last drug administration
Population: PKA
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| PBTZ169, 160 mg | Accumulation Ratios for the PK Parameters AUC(0 -24) | 1.50 ratio |
| PBTZ169, 320 mg | Accumulation Ratios for the PK Parameters AUC(0 -24) | 2.35 ratio |
| PBTZ169, 640 mg | Accumulation Ratios for the PK Parameters AUC(0 -24) | 2.74 ratio |
Secondary
AUC(0-24)
Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-24 hours\]
Time frame: Up to 24 hours after the first drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | AUC(0-24) | 93.604 ng*h/ml | Standard Deviation 74.3008 |
| PBTZ169, 320 mg | AUC(0-24) | 120.954 ng*h/ml | Standard Deviation 44.792 |
| PBTZ169, 640 mg | AUC(0-24) | 237.153 ng*h/ml | Standard Deviation 111.4025 |
Secondary
AUC(0-24)
Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-24 hours\] for the last dosing (Day 14)
Time frame: Up to 24 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | AUC(0-24) | 113.293 ng*h/ml | Standard Deviation 73.9862 |
| PBTZ169, 320 mg | AUC(0-24) | 349.308 ng*h/ml | Standard Deviation 282.1627 |
| PBTZ169, 640 mg | AUC(0-24) | 502.895 ng*h/ml | Standard Deviation 167.7201 |
Secondary
AUC(0-∞) of PBTZ169
Area under the plasma concentration versus time curve in frames \[0-∞\]
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | AUC(0-∞) of PBTZ169 | 141.855 ng*h/ml | Standard Deviation 87.0391 |
| PBTZ169, 320 mg | AUC(0-∞) of PBTZ169 | 412.819 ng*h/ml | Standard Deviation 299.2734 |
| PBTZ169, 640 mg | AUC(0-∞) of PBTZ169 | 568.581 ng*h/ml | Standard Deviation 189.4584 |
Secondary
AUC (0-t)
Area under the plasma concentration of PBTZ169 versus time curve in frames \[0-last concentration above lower limit of quantification (LLoQ)\]
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | AUC (0-t) | 113.259 ng*h/ml | Standard Deviation 73.9728 |
| PBTZ169, 320 mg | AUC (0-t) | 356.170 ng*h/ml | Standard Deviation 282.0489 |
| PBTZ169, 640 mg | AUC (0-t) | 502.075 ng*h/ml | Standard Deviation 168.5111 |
Secondary
Average Concentration (Css,av) of PBTZ169
Average steady-state concentration in the dosing interval following multiple dosing was evaluated as the ratio AUC0 24/τ (τ = the dosing interval)
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Average Concentration (Css,av) of PBTZ169 | 862.63 ng/ml | Standard Deviation 606.973 |
| PBTZ169, 320 mg | Average Concentration (Css,av) of PBTZ169 | 793.27 ng/ml | Standard Deviation 212.27 |
| PBTZ169, 640 mg | Average Concentration (Css,av) of PBTZ169 | 532.95 ng/ml | Standard Deviation 325.436 |
Secondary
Early Bactericidal Activity (0-2)
EBA (0-2): agar inoculation, the mean of two measurements at the Visit
Time frame: 2 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-2) | 0.496 CFU per 1 mL of sputum | Standard Deviation 0.615 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-2) | 0.124 CFU per 1 mL of sputum | Standard Deviation 0.095 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-2) | -0.003 CFU per 1 mL of sputum | Standard Deviation 0.452 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-2) | -0.243 CFU per 1 mL of sputum | Standard Deviation 0 |
Secondary
Early Bactericidal Activity (0-2)
EBA (0-2): PCR, the mean of two measurements at the Visit
Time frame: 2 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-2) | -0.110 cell count per 1 mL of sputum | Standard Deviation 0.872 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-2) | 0.007 cell count per 1 mL of sputum | Standard Deviation 0.084 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-2) | 0.085 cell count per 1 mL of sputum | Standard Deviation 0.397 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-2) | 0.627 cell count per 1 mL of sputum | Standard Deviation 0 |
Secondary
Early Bactericidal Activity (0-7)
EBA (0-7): agar inoculation, the mean of two measurements at the Visit
Time frame: 7 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-7) | 0.078 CFU per 1 mL of sputum | Standard Deviation 0.136 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-7) | 0.026 CFU per 1 mL of sputum | Standard Deviation 0.069 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-7) | 0.064 CFU per 1 mL of sputum | Standard Deviation 0.102 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-7) | 0.090 CFU per 1 mL of sputum | Standard Deviation 0 |
Secondary
Early Bactericidal Activity (0-7)
EBA (0-7): PCR, the mean of two measurements at the Visit
Time frame: 7 days after the onset of monotherapy
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Early Bactericidal Activity (0-7) | -0.044 cell count per 1 mL of sputum | Standard Deviation 0.076 |
| PBTZ169, 320 mg | Early Bactericidal Activity (0-7) | -0.004 cell count per 1 mL of sputum | Standard Deviation 0.081 |
| PBTZ169, 640 mg | Early Bactericidal Activity (0-7) | 0.116 cell count per 1 mL of sputum | Standard Deviation 0.186 |
| Isoniazid, 600 mg | Early Bactericidal Activity (0-7) | -0.408 cell count per 1 mL of sputum | Standard Deviation 0 |
Secondary
Elimination Constant (Kel) of PBTZ169
Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.
Time frame: 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Elimination Constant (Kel) of PBTZ169 | 0.0470 1/h | Standard Deviation 0.0123 |
| PBTZ169, 320 mg | Elimination Constant (Kel) of PBTZ169 | 0.0515 1/h | Standard Deviation 0.0098 |
| PBTZ169, 640 mg | Elimination Constant (Kel) of PBTZ169 | 0.0828 1/h | Standard Deviation 0.0211 |
Secondary
Elimination Constant (Kel) of PBTZ169
Apparent terminal elimination rate constant was evaluated based on the regressional dependence of log-transformed concentrations ln(C) on time for the terminal log- linear part of the concentration-time curve.
Time frame: 24 hours after the first drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Elimination Constant (Kel) of PBTZ169 | 0.0797 1/h | Standard Deviation 0.0371 |
| PBTZ169, 320 mg | Elimination Constant (Kel) of PBTZ169 | 0.0524 1/h | Standard Deviation 0.025 |
| PBTZ169, 640 mg | Elimination Constant (Kel) of PBTZ169 | 0.0708 1/h | Standard Deviation 0.0126 |
Secondary
Fluctuations (%) in the Dosing Interval
Fluctuations (%) in the dosing interval after multiple dosing ((Cmax - Cmin) × 100%/Css,av)
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Fluctuations (%) in the Dosing Interval | 32955.25 % (ratio) | Standard Deviation 18636.037 |
| PBTZ169, 320 mg | Fluctuations (%) in the Dosing Interval | 24703.16 % (ratio) | Standard Deviation 19047.811 |
| PBTZ169, 640 mg | Fluctuations (%) in the Dosing Interval | 16253.19 % (ratio) | Standard Deviation 7977.03 |
Secondary
Minimal Plasma Concentration (Сmin) of PBTZ169
Minimal plasma concentration (Сmin) of PBTZ169: multiple dosing
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 1.4207 ng/ml | Standard Deviation 1.0145 |
| PBTZ169, 320 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 3.3889 ng/ml | Standard Deviation 2.0001 |
| PBTZ169, 640 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 4.9322 ng/ml | Standard Deviation 2.4003 |
Secondary
Minimal Plasma Concentration (Сmin) of PBTZ169
Minimal plasma concentration (Сmin) of PBTZ169: concentration measurement following single dosing
Time frame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 0.4985 ng/ml | Standard Deviation 0.4475 |
| PBTZ169, 320 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 0.2678 ng/ml | Standard Deviation 0.3375 |
| PBTZ169, 640 mg | Minimal Plasma Concentration (Сmin) of PBTZ169 | 1.0275 ng/ml | Standard Deviation 0.9101 |
Secondary
Peak Plasma Concentration (Сmax) of PBTZ169
Peak plasma concentration (Сmax) of PBTZ169 for multiple dosing
Time frame: Up to 72 hours after the last drug administration
Population: PKA: the pharmacokinetic analysis population for multiple dosing comprised all patients participating in the PK study who had received at least one dose of the study drug PBTZ169, provided that data on study drug concentration (with at least one measurement above BLQ) was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 34.4714 ng/ml | Standard Deviation 18.6498 |
| PBTZ169, 320 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 122.0135 ng/ml | Standard Deviation 96.3347 |
| PBTZ169, 640 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 101.3818 ng/ml | Standard Deviation 31.383 |
Secondary
Peak Plasma Concentration (Сmax) of PBTZ169
Peak plasma concentration (Сmax) of PBTZ169: concentration measurement following single dosing
Time frame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
Population: PKA: the pharmacokinetic analysis population for multiple dosing comprised all patients participating in the PK study who had received at least one dose of the study drug PBTZ169, provided that data on study drug concentration (with at least one measurement above BLQ) was available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 24.6543 ng/ml | Standard Deviation 18.8506 |
| PBTZ169, 320 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 35.5370 ng/ml | Standard Deviation 23.4983 |
| PBTZ169, 640 mg | Peak Plasma Concentration (Сmax) of PBTZ169 | 79.6684 ng/ml | Standard Deviation 49.1865 |
Secondary
Plasma Half-life Time (T1/2) of PBTZ169
Time frame: 24 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 15.524 h | Standard Deviation 4.0037 |
| PBTZ169, 320 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 13.790 h | Standard Deviation 2.3234 |
| PBTZ169, 640 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 8.883 h | Standard Deviation 2.5338 |
Secondary
Plasma Half-life Time (T1/2) of PBTZ169
Time frame: 24 hours after the fist drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 10.201 h | Standard Deviation 4.6319 |
| PBTZ169, 320 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 16.469 h | Standard Deviation 9.5669 |
| PBTZ169, 640 mg | Plasma Half-life Time (T1/2) of PBTZ169 | 10.110 h | Standard Deviation 2.153 |
Secondary
Residual Concentration (Ctrough) of PBTZ169
Residual concentration (Ctrough) of PBTZ169, measured 24 hours after the first dose administration, prior to the last dose, and 24 hours after the last dose
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PBTZ169, 160 mg | Residual Concentration (Ctrough) of PBTZ169 | prior to the last dose (Ctrough_MD0) | 2.1610 ng/ml | Standard Deviation 1.6332 |
| PBTZ169, 160 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the first dose (Ctrough_SD24) | 0.7835 ng/ml | Standard Deviation 0.682 |
| PBTZ169, 160 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the last dose (Ctrough_MD24) | 1.4207 ng/ml | Standard Deviation 1.0145 |
| PBTZ169, 320 mg | Residual Concentration (Ctrough) of PBTZ169 | prior to the last dose (Ctrough_MD0) | 4.9505 ng/ml | Standard Deviation 1.405 |
| PBTZ169, 320 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the first dose (Ctrough_SD24) | 1.4116 ng/ml | Standard Deviation 1.2712 |
| PBTZ169, 320 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the last dose (Ctrough_MD24) | 2.9274 ng/ml | Standard Deviation 1.4535 |
| PBTZ169, 640 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the first dose (Ctrough_SD24) | 1.8712 ng/ml | Standard Deviation 0.9453 |
| PBTZ169, 640 mg | Residual Concentration (Ctrough) of PBTZ169 | 24 hours after the last dose (Ctrough_MD24) | 5.2710 ng/ml | Standard Deviation 2.5201 |
| PBTZ169, 640 mg | Residual Concentration (Ctrough) of PBTZ169 | prior to the last dose (Ctrough_MD0) | 18.2674 ng/ml | Standard Deviation 27.2441 |
Secondary
Time to Reach Maximum Concentration (Tmax) of PBTZ169
Time to reach maximum concentration (Tmax) of PBTZ169 after single oral administration in different doses
Time frame: for single dosing , Day 1 (24 h after 1st dose of PBTZ169)
Population: PKA
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PBTZ169, 160 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 1.250 h |
| PBTZ169, 320 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 2.250 h |
| PBTZ169, 640 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 2.000 h |
Secondary
Time to Reach Maximum Concentration (Tmax) of PBTZ169
Time to reach maximum concentration (Tmax) of PBTZ169 after multiple oral administration in different doses
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PBTZ169, 160 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 2.000 h |
| PBTZ169, 320 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 2.000 h |
| PBTZ169, 640 mg | Time to Reach Maximum Concentration (Tmax) of PBTZ169 | 1.500 h |
Secondary
Total (Plasma) Clearance (Clt) of PBTZ169
Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl\_t/F=D/AUC where D is the daily dose of the drug.
Time frame: 24 hours after the first drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 3293.80 L/h | Standard Deviation 3329.026 |
| PBTZ169, 320 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 2375.06 L/h | Standard Deviation 759.203 |
| PBTZ169, 640 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 2935.49 L/h | Standard Deviation 1382.371 |
Secondary
Total (Plasma) Clearance (Clt) of PBTZ169
Clt/F (apparent total clearance following single and multiple oral administration) was calculated using the following formula: Cl\_t/F=D/AUC where D is the daily dose of the drug.
Time frame: 24 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 1393.31 L/h | Standard Deviation 606.676 |
| PBTZ169, 320 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 1200.61 L/h | Standard Deviation 899.707 |
| PBTZ169, 640 mg | Total (Plasma) Clearance (Clt) of PBTZ169 | 1259.77 L/h | Standard Deviation 519.021 |
Secondary
Volume of Distribution (Vd) of PBTZ169
Distribution volume Vd for a dosing interval of 72 hours after the last dose
Time frame: Up to 72 hours after the last drug administration
Population: PKA
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PBTZ169, 160 mg | Volume of Distribution (Vd) of PBTZ169 | 4.7206 L | Standard Deviation 3.0828 |
| PBTZ169, 320 mg | Volume of Distribution (Vd) of PBTZ169 | 14.5545 L | Standard Deviation 11.7568 |
| PBTZ169, 640 mg | Volume of Distribution (Vd) of PBTZ169 | 20.9540 L | Standard Deviation 6.9883 |