This study is a randomized, double-blind, placebo-controlled, dose-escalation, first-in-human clinical trial in healthy adults, designed to assess the safety, tolerability, and PK characteristics of PSTB100 tablets.
This Phase I clinical trial is a randomized, double-blind, placebo-controlled, dose-escalation study consisting of two parts: Part1: Single Ascending Dose (SAD) study Part2: Multiple Ascending Dose (MAD) study The SAD part uses a single-center, randomized, double-blind, placebo-controlled, dose-escalation design to evaluate the safety, tolerability, and PK/PD profile of single oral doses of PSTB100 Tablets under fasting conditions in healthy adult subjects. The MAD part uses a single-center, randomized, double-blind, placebo-controlled, dose-escalation design to evaluate the safety, tolerability, and PK/PD profile of multiple oral doses of PSTB100 Tablets in healthy adults. In addition, one dose cohort (expected to be Cohort 8) will include assessments of PK/PD changes of PSTB100 in cerebrospinal fluid (CSF) after repeated dosing.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
68
PSTB100 tablets
dose 1 once daily, dose 2 once daily, dose 3 once daily
Nucleus Network Pty Ltd
Brisbane, Queensland, Australia
RECRUITINGTime to Reach Maximum Observed Plasma concentration (Tmax)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
Maximum Observed PSTB100 Plasma Concentration (Cmax)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
PSTB100 area under the plasma concentration-time curve (AUC0-24h, AUC0-t, AUC0-∞, etc.)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
Plasma clearance (CL/F)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
Plasma elimination half-life (T₁/₂)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
Mean residence time (MRT)
PK characteristics after single dose
Time frame: Part 1 : Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose Part 2 : Pre- dose to 12 hours, and 24 hours post Day 1 dose to be collected within 15 minutes pre Day 2 dose
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Steady-state time to peak (Tmax,ss)
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Steady-state peak concentration (Cmax,ss)
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Steady-state trough concentration (Cmin,ss)
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Average steady-state plasma concentration (Cav,ss)
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Area under the steady-state plasma concentration-time curve (AUCss)
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Fluctuation factor (DF) between trough and peak concentrations;
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Accumulation ratios Rac:Cmax
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Accumulation ratios Rac:AUC.
PK characteristics after multiple dose
Time frame: Pre- dose to 12 hours, 24 hours post day 1 dose, pre- day 4, pre- day 6, pre- day 7 to 24 hours post day 7 dose, 48 hours post day 7 dose.
Plasma Metabolite Identification
Metabolite identification and relative abundance analysis will be performed in plasma samples from one cohort (expected to be a dose cohort within SAD Cohort 4 or 5, and sampling time points are same as PK blood sampling time points)
Time frame: Pre- dose to 24 hours , 48 hours post dose, 72 hours post dose
Inflammatory Cytokine Markers
PD biomarkers related to systemic inflammation,including IP-10, hsCRP, IFN-β, and IL-6. Absolute and percentage changes from baseline will be calculated, and PD marker-time profiles will be plotted by dose cohort.
Time frame: Pre-dose PD blood sample (before first dose): to be collected within 1 hour pre-dose Pre-dose PD blood sample (before subsequent doses): to be collected within 15 minutes pre-dose
Cerebrospinal fluid (CSF)
CSF samples will be collected to measure PSTB100 concentrations in Cohort 8. The CSF-to-plasma concentration ratio (C/P ratio) will be calculated, and a C/P-time profile will be constructed. The CSF concentration-time profile will be derived from this ratio and the corresponding plasma concentration-time profile.
Time frame: 1 hours post-Day 7 dose, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours post Day 7 dose