Tuberculosis, Tuberculosis, Pulmonary
Conditions
Keywords
TB, Tuberculosis, TBI-223, Pulmonary Tuberculosis
Brief summary
Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) with a Food Effect Cohort to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults.
Detailed description
This study was a partially-blinded, placebo-controlled, randomized SAD study conducted at one study center. The primary objective of the study was to evaluate the safety and tolerability of single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects. The secondary objectives of the study were to determine the PK of TBI-223 and its metabolite M2 after single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects, and to compare the rate and extent of absorption of a single dose of TBI-223 oral suspension and TBI-223 tablet formulations when administered in healthy adult subjects either after a high-calorie, high-fat meal or in the fasting state. Safety was assessed throughout the study for all subjects. Safety assessments included physical examinations, vital signs, serial ECGs, cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).
Interventions
DRUGTBI-223 oral suspension
TBI-223 oral suspension, orally administered.
DRUGTBI-223 enteric capsule
TBI-223 enteric capsules filled with 150 mg of TBI-223 powder, orally administered.
DRUGTBI-223 SR Tablet Prototype 1
TBI-223 600 mg sustained-release (SR) tablet Prototype 1, orally administered.
DRUGTBI-223 SR Tablet Prototype 2
TBI-223 600 mg SR tablet Prototype 2, orally administered.
DRUGTBI-223 SR Tablet Prototype 3
TBI-223 900 mg SR tablet Prototype 3, orally administered.
DRUGTBI-223 IR Tablet
TBI-223 1000 mg immediate release (IR) tablet, orally administered
Placebo for TBI-223 oral Suspension; orally administered.
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
This study is partially blinded. The repeat cohort (3b) using a different dosage formulation in Part 1 and subjects in Part 2 will be non-randomized and unblinded.
Eligibility
Sex/Gender
ALL
Age
19 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: All volunteers must satisfy the following criteria to be considered for study participation: 1. Is a healthy adult male or female, 19 to 50 years of age (inclusive) at the time of screening. 2. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg. 3. Is medically healthy with no clinically significant screening results (e.g., laboratory profiles normal or up to Grade 1 per Division of Microbiology and Infectious Diseases Toxicity Tables), as deemed by the Investigator. 4. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing. 5. If assigned to receive study drug under fed conditions, is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required. Key
Exclusion criteria
1. History or presence of clinically significant cardiovascular (heart murmur), pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results. 2. Any presence of musculoskeletal toxicity (severe tenderness with marked impairment of activity, or frank necrosis). 3. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at screening. 4. QTcF interval \>450 msec for males or \>470 msec for females at screening, Day -1, or Day 1 (predose), or history of prolonged QT syndrome. For the triplicate 12-lead ECGs taken at screening and on Day -1, the average QTcF interval of the three 12-lead ECG recordings were used to determine qualification. 5. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a condition that was causative of sudden death (such as known coronary artery disease, congestive heart failure, or terminal cancer). 6. History of any of the following: * Serotonin syndrome * Seizures or seizure disorders, other than childhood febrile seizures * Brain surgery * History of head injury in the last 5 years * Any serious disorder of the nervous system particularly one that lowered the seizure threshold. 7. Lactose intolerant. 8. History of sensitivity or contraindication to use of linezolid, tedizolid, or any study investigational products
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events | Day 1 - Day 11 | A treatment-related adverse event (AE) is defined for this study as any AE classified as possibly, probably or certainly related to the study drug. Adverse events (AEs) for participants who received at least one dose of study treatment were collected from the signing of informed consent till the end of study visit. An Investigator reviewed each AE collected and assessed its relationship to drug treatment based on all available information at the time of the completion of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | AUC0-t will be calculated from plasma concentrations of TBI-223. Area under the plasma concentration-time curve from time-zero to the time of the last quantifiable concentration (Clast), as calculated by the linear trapezoidal rule. |
| Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Cmax will be calculated from plasma concentrations of TBI-223. Cmax is calculated as the maximum plasma concentration, determined directly from individual concentration-time- data |
| Time of the Maximum Plasma Concentrations (Tmax) | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Tmax will be calculated from plasma concentrations of TBI-223. |
| The Observed Terminal Elimination Half-life (t1/2) | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | T1/2 will be calculated from plasma concentrations of TBI-223 and calculated as T½ = ln(2)/λz |
| Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | AUC0-inf will be calculated from plasma concentrations of TBI-223 AND M2 and calculated as AUC0-inf = AUC0-t + Clast/λz, where λz is the apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration versus time curve |
| Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 1200 mg Dose of TBI-223 Oral Suspension under Fed (Test) and Fasted (Reference) Conditions (Part 1; Cohort 5) |
| Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions. | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as IR tablets, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 9; Test) and IR tablets, 2000 mg (2 x1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference) |
| Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as SR (Prototypes 1, 2, and 3) under Fed Conditions (Cohort 8; Test) and IR, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference) |
| Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as TBI-223 after 1800 mg SR tablets (Prototypes 1, 2, 3,) under Fed Conditions (Cohort 8; Test) and 2000 mg IR tablets (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 8; Reference) |
| Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations | predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product | Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 300 mg Dose of TBI-223 Capsule Formulation (Cohort 3 Repeat; Part 1; Test) and a Single 300 mg Dose of TBI-223 Oral Suspension (Cohort 3; Part 1; Reference). |
Countries
United States
Participant flow
Recruitment details
Cohort 3b, period 2, was added in protocol version 3.0. Some participants chose to return for period 2 and new participants were enrolled for period 2 of cohort 3b.
Participants by arm
| Arm | Count |
|---|---|
| TBI-223 Placebo Part 1 Single dose matching placebo for TBI-223 under fasted conditions
Placebo suspension: Placebo for TBI-223 oral Suspension; orally administered | 14 |
| TBI-223 50 mg Cohort 1, single dose of TBI-223 50 mg dosed under fasted conditions
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 6 |
| TBI-223 100 mg Cohort 2, single dose of TBI-223 100 mg dosed under fasted conditions
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 6 |
| TBI-223 300 mg Cohort 3a, Period 1 - single dose of TBI-223 300 mg oral suspension dosed under fasted conditions
Cohort 3b, Period 2 - participants in Cohort 3a were invited after a washout period to return for an additional single dose of TBI-223 300 mg as powder in enteric capsules dosed under fasted conditions | 8 |
| TBI-223 600 mg Cohort 4, single dose of TBI-223 600 mg dosed under fasted conditions
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 6 |
| TBI-223 1200 mg Cohort 5, Period 1, single dose of TBI-223 1200 mg dosed under fasted conditions
Cohort 5, Period 2, participants were invited to return after a washout period to continue in period 2 and receive a single dose of TBI-223 1200 mg oral suspension dosed under fed conditions.
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 8 |
| TBI-223 2000 mg Cohort 6, single dose of TBI-223 2000 mg dosed under fasted conditions
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 6 |
| TBI-223 2600 mg Cohort 7, single dose of TBI-223 2600 mg dosed under fasted conditions
TBI-223 oral suspension: TBI-223 oral suspension, orally administered. | 8 |
| TBI-223 3x600 mg SR-1 Tablet Cohort 8, arm 1 -Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 1 under fed conditions
TBI-223 SR Tablet Prototype 1: TBI-223 600 mg sustained-release (SR) tablet Prototype 1, orally administered. | 6 |
| TBI-223 3x600 mg SR-2 Tablet Cohort 8, arm 2 -Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 2 under fed conditions
TBI-223 SR Tablet Prototype 2: TBI-223 600 mg SR tablet Prototype 2, orally administered. | 6 |
| TBI-223 2x900 mg SR-3 Tablet Cohort 8, arm 3 -Single dose TBI-223 of 1800 mg (2 x 900 mg) sustained release (SR) tablet formulation 3 under fed conditions
TBI-223 SR Tablet Prototype 3: TBI-223 900 mg SR tablet Prototype 3, orally administered. | 6 |
| TBI-223 2x1000 mg IR Tablet Cohort 8, arm 4 -Single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fasted conditions
Cohort 9 - Participants from Cohort 8 arm 4 were invited to return and were administered a single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fed conditions
TBI-223 IR Tablet: TBI-223 1000 mg immediate release (IR) tablet, orally administered | 6 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 2 | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout Period | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | TBI-223 2x900 mg SR-3 Tablet | Total | TBI-223 2x1000 mg IR Tablet | TBI-223 3x600 mg SR-2 Tablet | TBI-223 3x600 mg SR-1 Tablet | TBI-223 2600 mg | TBI-223 2000 mg | TBI-223 1200 mg | TBI-223 600 mg | TBI-223 300 mg | TBI-223 100 mg | TBI-223 50 mg | TBI-223 Placebo |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 34.2 years STANDARD_DEVIATION 9.13 | 34.1 years STANDARD_DEVIATION 8.42 | 33.3 years STANDARD_DEVIATION 8.31 | 30.7 years STANDARD_DEVIATION 4.89 | 39.2 years STANDARD_DEVIATION 8.3 | 32.8 years STANDARD_DEVIATION 7.81 | 38.7 years STANDARD_DEVIATION 8.48 | 32.6 years STANDARD_DEVIATION 8.81 | 37.2 years STANDARD_DEVIATION 9.11 | 30 years STANDARD_DEVIATION 7.45 | 32.3 years STANDARD_DEVIATION 3.93 | 34.5 years STANDARD_DEVIATION 9.79 | 35.1 years STANDARD_DEVIATION 10.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 43 Participants | 4 Participants | 2 Participants | 2 Participants | 5 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 3 Participants | 2 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 43 Participants | 2 Participants | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 5 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 29 Participants | 1 Participants | 0 Participants | 3 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 54 Participants | 5 Participants | 6 Participants | 3 Participants | 7 Participants | 3 Participants | 4 Participants | 4 Participants | 5 Participants | 4 Participants | 1 Participants | 8 Participants |
| Region of Enrollment United States | 6 participants | 86 participants | 6 participants | 6 participants | 6 participants | 8 participants | 6 participants | 8 participants | 6 participants | 8 participants | 6 participants | 6 participants | 14 participants |
| Sex: Female, Male Female | 4 Participants | 42 Participants | 1 Participants | 4 Participants | 4 Participants | 5 Participants | 2 Participants | 5 Participants | 4 Participants | 6 Participants | 2 Participants | 3 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 44 Participants | 5 Participants | 2 Participants | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 12 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 | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 7 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
| other Total, other adverse events | 4 / 14 | 1 / 6 | 2 / 6 | 1 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 1 / 7 | 3 / 6 | 3 / 8 | 1 / 6 | 2 / 6 | 2 / 6 | 3 / 6 | 2 / 6 |
| serious Total, serious adverse events | 0 / 14 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 8 | 0 / 7 | 0 / 6 | 0 / 8 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events
A treatment-related adverse event (AE) is defined for this study as any AE classified as possibly, probably or certainly related to the study drug. Adverse events (AEs) for participants who received at least one dose of study treatment were collected from the signing of informed consent till the end of study visit. An Investigator reviewed each AE collected and assessed its relationship to drug treatment based on all available information at the time of the completion of the study.
Time frame: Day 1 - Day 11
Population: All participants who received at least one dose of study treatment. Note: participants are divided here into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. This puts some participants into more than one analysis group based on the design of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TBI-223 Placebo | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 50 mg | Number of Participants With Treatment-related Adverse Events | 1 Participants |
| TBI-223 100 mg | Number of Participants With Treatment-related Adverse Events | 1 Participants |
| TBI-223 300 mg Oral Suspension | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 300 mg Oral Enteric Capsules | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 600 mg | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 1200 mg Fasted | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 1200 mg Fed | Number of Participants With Treatment-related Adverse Events | 1 Participants |
| TBI-223 2000 mg | Number of Participants With Treatment-related Adverse Events | 2 Participants |
| TBI-223 2600 mg | Number of Participants With Treatment-related Adverse Events | 3 Participants |
| TBI-223 3x600 mg SR-1 Tablet | Number of Participants With Treatment-related Adverse Events | 1 Participants |
| TBI-223 3x600 mg SR-2 Tablet | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 2x900 mg SR-3 Tablet | Number of Participants With Treatment-related Adverse Events | 0 Participants |
| TBI-223 2x1000 mg IR Tablet Fasted | Number of Participants With Treatment-related Adverse Events | 3 Participants |
| TBI-223 2x1000 mg IR Tablet Fed | Number of Participants With Treatment-related Adverse Events | 2 Participants |
Secondary
Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf)
AUC0-inf will be calculated from plasma concentrations of TBI-223 AND M2 and calculated as AUC0-inf = AUC0-t + Clast/λz, where λz is the apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration versus time curve
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Participants are divided into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. Some participants are in more than one analysis group based on the design of the study. Two subjects from Cohort 7 experienced emesis at 1.17 h and 1.37 h, respectively, after dosing. Data for these subjects were excluded from analyses of PK outcome measures. AUCs for SR-1, SR-2, and SR-3 were normalized to the 2000 mg dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TBI-223 Placebo | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 1640 h*ng/mL | Standard Deviation 344 |
| TBI-223 Placebo | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 663 h*ng/mL | Standard Deviation 106 |
| TBI-223 50 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 2730 h*ng/mL | Standard Deviation 628 |
| TBI-223 50 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 1080 h*ng/mL | Standard Deviation 178 |
| TBI-223 100 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 10700 h*ng/mL | Standard Deviation 2100 |
| TBI-223 100 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 4640 h*ng/mL | Standard Deviation 881 |
| TBI-223 300 mg Oral Suspension | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 8690 h*ng/mL | Standard Deviation 1690 |
| TBI-223 300 mg Oral Suspension | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 4020 h*ng/mL | Standard Deviation 511 |
| TBI-223 300 mg Oral Enteric Capsules | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 8889 h*ng/mL | Standard Deviation 2020 |
| TBI-223 300 mg Oral Enteric Capsules | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 25500 h*ng/mL | Standard Deviation 9580 |
| TBI-223 600 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 15900 h*ng/mL | Standard Deviation 2660 |
| TBI-223 600 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 45000 h*ng/mL | Standard Deviation 13800 |
| TBI-223 1200 mg Fasted | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 47700 h*ng/mL | Standard Deviation 14300 |
| TBI-223 1200 mg Fasted | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 15800 h*ng/mL | Standard Deviation 2580 |
| TBI-223 1200 mg Fed | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 107000 h*ng/mL | Standard Deviation 17800 |
| TBI-223 1200 mg Fed | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 32900 h*ng/mL | Standard Deviation 7340 |
| TBI-223 2000 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 36700 h*ng/mL | Standard Deviation 4800 |
| TBI-223 2000 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 127000 h*ng/mL | Standard Deviation 37800 |
| TBI-223 2600 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 22700 h*ng/mL | Standard Deviation 5350 |
| TBI-223 2600 mg | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 71300 h*ng/mL | Standard Deviation 18800 |
| TBI-223 3x600 mg SR-1 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 22700 h*ng/mL | Standard Deviation 4770 |
| TBI-223 3x600 mg SR-1 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 69500 h*ng/mL | Standard Deviation 16000 |
| TBI-223 3x600 mg SR-2 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 28400 h*ng/mL | Standard Deviation 7240 |
| TBI-223 3x600 mg SR-2 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 82600 h*ng/mL | Standard Deviation 19400 |
| TBI-223 2x900 mg SR-3 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 86400 h*ng/mL | Standard Deviation 21200 |
| TBI-223 2x900 mg SR-3 Tablet | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 25100 h*ng/mL | Standard Deviation 3790 |
| TBI-223 2x1000 mg IR Tablet Fasted | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | M2 | 26000 h*ng/mL | Standard Deviation 3540 |
| TBI-223 2x1000 mg IR Tablet Fasted | Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf) | TBI-223 | 100000 h*ng/mL | Standard Deviation 27300 |
Secondary
AUC0-t
AUC0-t will be calculated from plasma concentrations of TBI-223. Area under the plasma concentration-time curve from time-zero to the time of the last quantifiable concentration (Clast), as calculated by the linear trapezoidal rule.
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Two subjects from Cohort 7 experienced emesis at 1.17 h and 1.37 h, respectively, after dosing. Data for these subjects were excluded from analyses of PK outcome measures. AUCs for SR-1, SR-2, and SR-3 were normalized to the 2000 mg dose. Participants are divided into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. Some participants are in more than one analysis group based on the design of the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TBI-223 Placebo | AUC0-t | M2 | 633 h*ng/mL | Standard Deviation 108 |
| TBI-223 Placebo | AUC0-t | TBI-223 | 1620 h*ng/mL | Standard Deviation 343 |
| TBI-223 50 mg | AUC0-t | TBI-223 | 2730 h*ng/mL | Standard Deviation 631 |
| TBI-223 50 mg | AUC0-t | M2 | 1050 h*ng/mL | Standard Deviation 177 |
| TBI-223 100 mg | AUC0-t | M2 | 4610 h*ng/mL | Standard Deviation 885 |
| TBI-223 100 mg | AUC0-t | TBI-223 | 10700 h*ng/mL | Standard Deviation 2090 |
| TBI-223 300 mg Oral Suspension | AUC0-t | TBI-223 | 8640 h*ng/mL | Standard Deviation 1690 |
| TBI-223 300 mg Oral Suspension | AUC0-t | M2 | 3980 h*ng/mL | Standard Deviation 516 |
| TBI-223 300 mg Oral Enteric Capsules | AUC0-t | TBI-223 | 25500 h*ng/mL | Standard Deviation 9560 |
| TBI-223 300 mg Oral Enteric Capsules | AUC0-t | M2 | 8850 h*ng/mL | Standard Deviation 2020 |
| TBI-223 600 mg | AUC0-t | M2 | 16400 h*ng/mL | Standard Deviation 2840 |
| TBI-223 600 mg | AUC0-t | TBI-223 | 45900 h*ng/mL | Standard Deviation 13000 |
| TBI-223 1200 mg Fasted | AUC0-t | TBI-223 | 47600 h*ng/mL | Standard Deviation 14300 |
| TBI-223 1200 mg Fasted | AUC0-t | M2 | 15800 h*ng/mL | Standard Deviation 2590 |
| TBI-223 1200 mg Fed | AUC0-t | M2 | 32800 h*ng/mL | Standard Deviation 7340 |
| TBI-223 1200 mg Fed | AUC0-t | TBI-223 | 107000 h*ng/mL | Standard Deviation 17800 |
| TBI-223 2000 mg | AUC0-t | TBI-223 | 127000 h*ng/mL | Standard Deviation 37700 |
| TBI-223 2000 mg | AUC0-t | M2 | 36600 h*ng/mL | Standard Deviation 4790 |
| TBI-223 2600 mg | AUC0-t | TBI-223 | 71000 h*ng/mL | Standard Deviation 18900 |
| TBI-223 2600 mg | AUC0-t | M2 | 22500 h*ng/mL | Standard Deviation 5420 |
| TBI-223 3x600 mg SR-1 Tablet | AUC0-t | M2 | 22600 h*ng/mL | Standard Deviation 4770 |
| TBI-223 3x600 mg SR-1 Tablet | AUC0-t | TBI-223 | 69400 h*ng/mL | Standard Deviation 16000 |
| TBI-223 3x600 mg SR-2 Tablet | AUC0-t | TBI-223 | 82600 h*ng/mL | Standard Deviation 19400 |
| TBI-223 3x600 mg SR-2 Tablet | AUC0-t | M2 | 28300 h*ng/mL | Standard Deviation 7230 |
| TBI-223 2x900 mg SR-3 Tablet | AUC0-t | TBI-223 | 86300 h*ng/mL | Standard Deviation 21200 |
| TBI-223 2x900 mg SR-3 Tablet | AUC0-t | M2 | 25100 h*ng/mL | Standard Deviation 3800 |
| TBI-223 2x1000 mg IR Tablet Fasted | AUC0-t | TBI-223 | 100000 h*ng/mL | Standard Deviation 27300 |
| TBI-223 2x1000 mg IR Tablet Fasted | AUC0-t | M2 | 26000 h*ng/mL | Standard Deviation 3530 |
Secondary
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions
Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 1200 mg Dose of TBI-223 Oral Suspension under Fed (Test) and Fasted (Reference) Conditions (Part 1; Cohort 5)
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: All participants who enrolled in cohort 5 and received TBI-223. Participants in period 1 were invited to participate in period 2.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions | Cmax | 103.34 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions | AUC0-t | 103.23 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions | AUC0-inf | 102.79 ratio (%) |
Secondary
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions
Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as TBI-223 after 1800 mg SR tablets (Prototypes 1, 2, 3,) under Fed Conditions (Cohort 8; Test) and 2000 mg IR tablets (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 8; Reference)
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: SR-1, SR-2, and SR-3 parameters were dose-normalized to 2000 mg prior to analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-t | 70.09 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | Cmax | 35.39 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-inf | 70.45 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-t | 69.60 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | Cmax | 47.41 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-inf | 69.62 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | Cmax | 43.85 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-inf | 82.74 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions | AUC0-t | 82.70 ratio (%) |
Secondary
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions.
Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as IR tablets, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 9; Test) and IR tablets, 2000 mg (2 x1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference)
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: All participants who enrolled were enrolled in cohort 8, arm 4 and were also enrolled in cohort 9.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions. | Cmax | 151.24 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions. | AUC0-t | 115.73 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions. | ACU0-inf | 115.70 ratio (%) |
Secondary
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations
Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 300 mg Dose of TBI-223 Capsule Formulation (Cohort 3 Repeat; Part 1; Test) and a Single 300 mg Dose of TBI-223 Oral Suspension (Cohort 3; Part 1; Reference).
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Participants enrolled in cohort 3a and cohort 3b who received TBI-223. Participants from cohort 3a were invited to participate in cohort 3b and additional participants were enrolled in 3b to replace those who elected not to participate.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations | Cmax | 42.46 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations | AUC0-t | 94.43 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations | AUC0-inf | 94.73 ratio (%) |
Secondary
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions
Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as SR (Prototypes 1, 2, and 3) under Fed Conditions (Cohort 8; Test) and IR, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference)
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: SR-1, SR-2, and SR-3 parameters were dose-normalized to 2000 mg prior to analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC0-t | 81.11 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | Cmax | 53.53 ratio (%) |
| TBI-223 Placebo | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC 0-inf | 81.52 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC0-t | 80.55 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | Cmax | 71.70 ratio (%) |
| TBI-223 50 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC 0-inf | 80.56 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | Cmax | 66.31 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC 0-inf | 95.73 ratio (%) |
| TBI-223 100 mg | Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions | AUC0-t | 95.71 ratio (%) |
Secondary
Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax)
Cmax will be calculated from plasma concentrations of TBI-223. Cmax is calculated as the maximum plasma concentration, determined directly from individual concentration-time- data
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Participants are divided into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. Some participants are in more than one analysis group based on the design of the study. Two subjects from Cohort 7 experienced emesis at 1.17 h and 1.37 h, respectively, after dosing. Data for these subjects were excluded from analyses of PK outcome measures. Cmax for SR-1, SR-2, and SR-3 were normalized to the 2000 mg dose.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TBI-223 Placebo | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 506 ng/mL | Standard Deviation 156 |
| TBI-223 Placebo | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 109 ng/mL | Standard Deviation 15.7 |
| TBI-223 50 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 811 ng/mL | Standard Deviation 201 |
| TBI-223 50 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 196 ng/mL | Standard Deviation 31.3 |
| TBI-223 100 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 3090 ng/mL | Standard Deviation 664 |
| TBI-223 100 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 897 ng/mL | Standard Deviation 195 |
| TBI-223 300 mg Oral Suspension | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 1360 ng/mL | Standard Deviation 610 |
| TBI-223 300 mg Oral Suspension | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 489 ng/mL | Standard Deviation 137 |
| TBI-223 300 mg Oral Enteric Capsules | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 1410 ng/mL | Standard Deviation 397 |
| TBI-223 300 mg Oral Enteric Capsules | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 5800 ng/mL | Standard Deviation 2400 |
| TBI-223 600 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 2240 ng/mL | Standard Deviation 345 |
| TBI-223 600 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 8530 ng/mL | Standard Deviation 1030 |
| TBI-223 1200 mg Fasted | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 9150 ng/mL | Standard Deviation 2740 |
| TBI-223 1200 mg Fasted | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 2210 ng/mL | Standard Deviation 399 |
| TBI-223 1200 mg Fed | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 14800 ng/mL | Standard Deviation 2650 |
| TBI-223 1200 mg Fed | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 3550 ng/mL | Standard Deviation 871 |
| TBI-223 2000 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 3650 ng/mL | Standard Deviation 772 |
| TBI-223 2000 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 16200 ng/mL | Standard Deviation 4640 |
| TBI-223 2600 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 1830 ng/mL | Standard Deviation 557 |
| TBI-223 2600 mg | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 7040 ng/mL | Standard Deviation 2010 |
| TBI-223 3x600 mg SR-1 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 2430 ng/mL | Standard Deviation 657 |
| TBI-223 3x600 mg SR-1 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 9580 ng/mL | Standard Deviation 3390 |
| TBI-223 3x600 mg SR-2 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 2480 ng/mL | Standard Deviation 499 |
| TBI-223 3x600 mg SR-2 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 8490 ng/mL | Standard Deviation 1670 |
| TBI-223 2x900 mg SR-3 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 12800 ng/mL | Standard Deviation 2320 |
| TBI-223 2x900 mg SR-3 Tablet | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 2770 ng/mL | Standard Deviation 499 |
| TBI-223 2x1000 mg IR Tablet Fasted | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | M2 | 3620 ng/mL | Standard Deviation 847 |
| TBI-223 2x1000 mg IR Tablet Fasted | Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax) | TBI-223 | 19700 ng/mL | Standard Deviation 5640 |
Secondary
The Observed Terminal Elimination Half-life (t1/2)
T1/2 will be calculated from plasma concentrations of TBI-223 and calculated as T½ = ln(2)/λz
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Participants are divided here into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. This puts some participants into more than one analysis group based on the design of the study. Two subjects from Cohort 7 experienced emesis at 1.17 h and 1.37 h, respectively, after dosing. Data for these subjects were excluded from analyses of PK outcome measures.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TBI-223 Placebo | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.19 hours | Standard Deviation 0.239 |
| TBI-223 Placebo | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.62 hours | Standard Deviation 0.256 |
| TBI-223 50 mg | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 1.96 hours | Standard Deviation 0.165 |
| TBI-223 50 mg | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.41 hours | Standard Deviation 0.238 |
| TBI-223 100 mg | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 1.94 hours | Standard Deviation 0.238 |
| TBI-223 100 mg | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.25 hours | Standard Deviation 0.403 |
| TBI-223 300 mg Oral Suspension | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 3.43 hours | Standard Deviation 1.02 |
| TBI-223 300 mg Oral Suspension | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.93 hours | Standard Deviation 1.36 |
| TBI-223 300 mg Oral Enteric Capsules | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.17 hours | Standard Deviation 0.585 |
| TBI-223 300 mg Oral Enteric Capsules | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.63 hours | Standard Deviation 0.693 |
| TBI-223 600 mg | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.33 hours | Standard Deviation 0.635 |
| TBI-223 600 mg | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.93 hours | Standard Deviation 0.706 |
| TBI-223 1200 mg Fasted | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.32 hours | Standard Deviation 0.158 |
| TBI-223 1200 mg Fasted | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.72 hours | Standard Deviation 0.207 |
| TBI-223 1200 mg Fed | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 3.81 hours | Standard Deviation 0.87 |
| TBI-223 1200 mg Fed | The Observed Terminal Elimination Half-life (t1/2) | M2 | 4.44 hours | Standard Deviation 0.698 |
| TBI-223 2000 mg | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.74 hours | Standard Deviation 0.752 |
| TBI-223 2000 mg | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.93 hours | Standard Deviation 0.534 |
| TBI-223 2600 mg | The Observed Terminal Elimination Half-life (t1/2) | M2 | 4.21 hours | Standard Deviation 2.45 |
| TBI-223 2600 mg | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 3.70 hours | Standard Deviation 0.271 |
| TBI-223 3x600 mg SR-1 Tablet | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.77 hours | Standard Deviation 0.728 |
| TBI-223 3x600 mg SR-1 Tablet | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.32 hours | Standard Deviation 0.581 |
| TBI-223 3x600 mg SR-2 Tablet | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.61 hours | Standard Deviation 0.843 |
| TBI-223 3x600 mg SR-2 Tablet | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 3.08 hours | Standard Deviation 0.784 |
| TBI-223 2x900 mg SR-3 Tablet | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.80 hours | Standard Deviation 0.604 |
| TBI-223 2x900 mg SR-3 Tablet | The Observed Terminal Elimination Half-life (t1/2) | M2 | 3.24 hours | Standard Deviation 0.604 |
| TBI-223 2x1000 mg IR Tablet Fasted | The Observed Terminal Elimination Half-life (t1/2) | M2 | 2.97 hours | Standard Deviation 0.325 |
| TBI-223 2x1000 mg IR Tablet Fasted | The Observed Terminal Elimination Half-life (t1/2) | TBI-223 | 2.38 hours | Standard Deviation 0.101 |
Secondary
Time of the Maximum Plasma Concentrations (Tmax)
Tmax will be calculated from plasma concentrations of TBI-223.
Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product
Population: Participants are divided here into analysis groups based on the drug and formulation taken and fed vs fasted status at dosing. This puts some participants into more than one analysis group based on the design of the study. Two subjects from Cohort 7 experienced emesis at 1.17 h and 1.37 h, respectively, after dosing. Data for these subjects were excluded from analyses of PK outcome measures.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TBI-223 Placebo | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.0 hours |
| TBI-223 Placebo | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 1.00 hours |
| TBI-223 50 mg | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.50 hours |
| TBI-223 50 mg | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 1.50 hours |
| TBI-223 100 mg | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.37 hours |
| TBI-223 100 mg | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 1.50 hours |
| TBI-223 300 mg Oral Suspension | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 5.00 hours |
| TBI-223 300 mg Oral Suspension | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 5.50 hours |
| TBI-223 300 mg Oral Enteric Capsules | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 2.50 hours |
| TBI-223 300 mg Oral Enteric Capsules | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.75 hours |
| TBI-223 600 mg | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 3.00 hours |
| TBI-223 600 mg | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.50 hours |
| TBI-223 1200 mg Fasted | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.50 hours |
| TBI-223 1200 mg Fasted | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 3.00 hours |
| TBI-223 1200 mg Fed | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 1.52 hours |
| TBI-223 1200 mg Fed | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 3.50 hours |
| TBI-223 2000 mg | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 4.00 hours |
| TBI-223 2000 mg | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 2.25 hours |
| TBI-223 2600 mg | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 7.50 hours |
| TBI-223 2600 mg | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 7.00 hours |
| TBI-223 3x600 mg SR-1 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 7.50 hours |
| TBI-223 3x600 mg SR-1 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 6.50 hours |
| TBI-223 3x600 mg SR-2 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 8.00 hours |
| TBI-223 3x600 mg SR-2 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 7.50 hours |
| TBI-223 2x900 mg SR-3 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 2.00 hours |
| TBI-223 2x900 mg SR-3 Tablet | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 3.00 hours |
| TBI-223 2x1000 mg IR Tablet Fasted | Time of the Maximum Plasma Concentrations (Tmax) | M2 | 3.00 hours |
| TBI-223 2x1000 mg IR Tablet Fasted | Time of the Maximum Plasma Concentrations (Tmax) | TBI-223 | 3.00 hours |