A Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults

Study Overview
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Brief Summary
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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
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In Part 1, up to 50 subjects in 6 dosing cohorts are planned to be enrolled; within each cohort, 6 subjects will be assigned to active treatment and 2 to placebo. Each subject will participate in one dose level. Based on interim pharmacokinetic data obtained during the dose escalation, a dose cohort will be selected to return for additional dosing after a high-calorie, high-fat meal (food-effect cohort). Each cohort will be dosed in two groups in order to monitor subjects for adverse experiences, in particular, convulsions (in the dog toxicity studies, tremors were observed at Cmax or plasma concentration of ≥82µg/mL, and convulsions were observed at plasma concentration or Cmax of ≥ 158µg/mL). In the first cohort, a sentinel group of 3 subjects (2 active and 1 placebo) will be dosed at least 24 hours before the remaining 5 subjects (4 active and 1 placebo). The remaining cohorts will be dosed in 2 groups of 4 subjects each (3 active and 1 placebo), at least 24 hours apart. One cohort (10 subjects) will be brought back to receive a dose (8 active and 2 placebo) under fed conditions (Food-effect Cohort). In Part 2, it is planned to enroll a minimum of 24 subjects in a total of four arms with 6 subjects each. Each group of 6 subjects will receive a single dose of 1 of 3 sustained release (SR) tablet formulations of TBI-223 under fed conditions, and one will receive an immediate release (IR) formulation under fasted conditions.The group that received the IR formulation will be brought back later to receive the same formulation under fed conditions. Additional cohorts may be enrolled if deemed appropriate (e.g., if bioavailability is lower than expected) by the Sponsor to repeat a dose level, to study other dose levels, change proposed cohorts, or to study a different dosage formulation. These decisions regarding changed or additional cohorts will not take place until the Sponsor, in conjunction with the Principal Investigator and dose escalating committee, has determined that adequate safety, tolerability, and pharmacokinetics from the previous cohort have been demonstrated to permit proceeding to the next cohort. The Institutional Review Board (IRB) should be immediately notified of this revised approach for review and approval. Safety will be assessed throughout the study for all subjects. Safety assessments will include physical and neurological examinations, vital signs, electrocardiograms (ECGs), cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis). Blood and urine will be collected for clinical laboratory evaluations. Female subjects will have blood collected for serum pregnancy testing. Postmenopausal females will have blood collected to measure follicle-stimulating hormone (FSH) levels. Blood will be collected for pharmacokinetic analysis. Dose escalation to the next cohort (i.e., dose level) will not take place until the Sponsor, in conjunction with the Principal Investigator, has determined that adequate safety, tolerability and pharmacokinetic data from the previous cohorts have been demonstrated to permit proceeding to the next cohort. The Principal Investigator, in conjunction with the Sponsor may collect additional blood if necessary, for repeat laboratory or safety evaluations including AE follow up. The study will be conducted at one study center in the United States.This study will have up to 6 planned dose levels. Based on interim pharmacokinetic data obtained during the dose escalation, a dose cohort will be selected to return for additional dosing after a high calorie, high-fat meal (Food-effect Cohort). Trial Monitoring: Sponsor personnel (or designees) will be responsible for monitoring the study to ensure compliance with the protocol and Good Clinical Practices (GCP). Compliance may be verified by one or more of the following methods: on-site visits, frequent communication with the Investigator, and/or review of case report forms (CRFs) and source documents. The Investigator agrees to permit such monitoring as well as audits or reviews by regulatory authorities and the IRB. Safety Monitoring and Procedures: Subjects will be instructed to inform the study physician and/or research personnel of any AEs that occur at any time during the study. Subjects will be monitored for AEs from the first dose through the end-of-study visit. Adverse Events: The Investigator or a suitably medically qualified designee are responsible for eliciting adverse events by observing and questioning the subject and recording all adverse events observed by him/her or reported by the subject during the trial. Serious Adverse Event (SAE) Reporting:The Investigator or designee will notify the appropriate Sponsor contact immediately after the SAE detection, observation, or report of occurrence (regardless of the relationship to test article). Analytical Methodology: Plasma samples will be analyzed for TBI-223 and M2 using validated assays. Plasma samples from subjects who receive placebo for TBI-223 oral suspension will not be analyzed. Statistical Analysis: : Final statistical analyses will be performed using appropriate software, e.g. Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with the internet-accessible implementation of Pharsight® Knowledgebase Server™ [PKSO; Version 4.0.4 or higher, Certara, L.P.]) and/or SAS® (Version 9.4 or higher, SAS Institute Inc.). Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. Summary statistics will also be presented by gender within each cohort. Dose proportionality will be assessed using a power model approach. Food-effect cohort: The effect of food will be assessed comparing pharmacokinetic parameters (maximum plasma concentration (Cmax), area under plasma concentration versus time curves (AUCs)) under fed versus fasting conditions using an analysis of variance (ANOVA) approach.

Official Title
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A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) With a Food Effect Cohort Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult Participants.

Conditions
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Tuberculosis, Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: TBI-223 50mg
* Drug: Placebo for TBI-223 50mg
* Drug: TBI-223 100, 300, 600, 1200, 2000, 2600 mg
* Drug: Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg
* Drug: TBI-223 300 mg capsule
* Drug: Placebo for TBI-223 300 mg capsule
* Drug: TBI-223 Prototype 1 SR Tablet
* Drug: TBI-223 Prototype 2 SR Tablet
* Drug: TBI-223 Prototype 3 SR Tablet
* Drug: TBI-223 IR Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All volunteers must satisfy the following criteria to be considered for study participation: Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures. Is a healthy adult male or a healthy adult female of non-childbearing potential, 19 to 50 years of age (inclusive) at the time of screening. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg. Is medically healthy with no clinically significant screening results, as determined by the Principal Investigator (e.g., laboratory profiles are normal up to and including Grade 1 per DMID toxicity tables; Appendix 3), medical history, vital signs, ECG, or physical/neurological examination findings. Note: If exclusionary lab criteria are met, values may be confirmed by repeat evaluation. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing. If female, she has undergone one of the following sterilization procedures at least 6 months before dosing: Hysteroscopic sterilization; Bilateral tubal ligation or bilateral salpingectomy; Hysterectomy; or Bilateral oophorectomy; Or is postmenopausal with amenorrhea for at least 1 year before the first dose with serum follicle-stimulating hormone (FSH) levels consistent with postmenopausal status (i.e., greater than 40 mIU/mL) at screening. Or, if female of childbearing potential, must agree to use an allowable form of birth control from screening until 14 days after study completion. The following are allowed birth control methods for this study: Vasectomized partner (at least 6 months before dosing); Non-surgical permanent sterilization (e.g., Essure procedure) at least 3 months before dosing; Double barrier method (e.g., diaphragm with spermicide; condoms with spermicide); Intrauterine device (IUD); Abstinence (and must agree to use a double barrier method if they become sexually active during the study); Implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive months before study dosing; and/or Oral, patch, or injected contraceptives, or vaginal hormonal device (NuvaRing), in use for at least 3 consecutive months before study dosing. If a non-vasectomized male (or male vasectomized less than 120 days prior to study start) he must agree to the following during study participation and for 90 days after the last administration of study drug: Use a condom with spermicide while engaging in sexual activity or be sexually abstinent, Not donate sperm during this time. In the event the sexual partner is surgically sterile or postmenopausal, use of a condom with spermicide is not necessary. None of the birth control restrictions listed above are required for vasectomized males whose procedure was performed more than 120 days before study start. Is willing to answer inclusion and exclusion criteria questionnaire at check-in. Is able to comply with the protocol and the assessments therein, including all restrictions. Is willing and able to remain in the study unit for the entire duration of the assigned confinement period(s), return for outpatient visit(s), and receive a phone call for follow-up questioning about AEs. If enrolled in the food-effect cohort, is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required. Exclusion Criteria: Volunteers will be excluded from study participation for any of the following: History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological (including epilepsy), oncologic, or 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. Evidence on physical exam and targeted neurologic exam of specific findings such as resting or intention tremor, dysmetria, nystagmus or ataxia, or abnormal deep tendon reflexes (either zero or hyper-reflexia). History of any illness that, in the opinion of the Investigator, might confound the results of the study or pose an additional risk to the subject by their participation in the study. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant, or any history of cholecystectomy. History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant. History of sensitivity or contraindication to use of linezolid, sulfa drugs, or any study investigational products. Participation in another clinical trial within 30 days prior to dosing. Female subjects who are pregnant or lactating. Positive result on a urine drug/alcohol/cotinine screen at Baseline or check-in. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. Out-of-range vital signs may be repeated once for confirmation. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. Out-of-range vital signs may be repeated once for confirmation. Any clinically significant ECG abnormality at Screening (as deemed by decision of the Investigator and the Sponsor's Medical Monitor). NOTE: The following may be considered not clinically significant without consulting the Sponsor's Medical Monitor: Mild first degree A-V block (P-R interval <0.23 sec) Right or left axis deviation Incomplete right bundle branch block Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects Early repolarization Tall T waves RSR in V1/V2 consistent with right ventricular conduction delay (with acceptable QRS) Sinus rhythm or sinus bradycardia with sinus arrhythmia Minimal or moderate voltage criteria for left ventricular hypertrophy (LVH). QTcF interval >450 msec for males or >470 msec for females at screening, Day -1, or Day 1 (pre-dose), or history of prolonged QT syndrome. For the triplicate ECGs taken at screening and on Day -1, the average QTcF interval of the three ECG recordings will be used to determine qualification. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a condition that could be causative of sudden death (such as known coronary artery disease, congestive heart failure, or terminal cancer). History of one or any combination of, the following: 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 central nervous system (CNS) or related neurological system, particularly one that may lower the seizure threshold. Lactose intolerant. History or presence of allergic or adverse response to Listerine breath strips or aspartame. Specific Treatments Use of any prescription medication within 14 days prior to dosing. Use of any of the following medications within 30 days before the first dose of study drug or during the study drug treatment period: monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc.), antipsychotics such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, etc.), bupropion, agents known to prolong the QTc interval (erythromycin, clarithromycin, astemizole, type Ia [quinidine, procainamide, disopyramide] and III [amiodarone, sotalol] anti-arrhythmics, carbamazepine, sulfonylureas, and meperidine). Use of any over-the-counter (OTC) medication, including herbal products and vitamins, within 7 days prior to dosing, except acetaminophen. Up to 3 grams per day of acetaminophen is allowed at the discretion of the Investigator prior to dosing. Use of any drugs or substances known to be significant inhibitors of cytochrome P450 (CYP) enzymes and/or significant inhibitors or substrates of P-glycoprotein (P-gp) and/or organic anion transporting polypeptides (OATP) within 14 days prior to the first dose of study drug. Use of any drugs or substances known to be inducers of CYP enzymes and/or Pgp, including St. John's Wort, within 30 days prior to the first dose of study drug. Use of any drugs or substance known to lower the seizure threshold. Laboratory Abnormalities Serum magnesium, potassium, or calcium laboratory values outside of the normal range at screening. If exclusionary lab criteria are met, values may be confirmed by repeat evaluation. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1 (sentinel group) - Active<br>Single dose of TBI-223 50 mg (n=2) dosed at least 24 hours before the Cohort 1 (remainder of cohort). | Drug: TBI-223 50mg<br>* TBI-223 50 mg supplied for oral administration.<br>|
| Placebo Comparator: Cohort 1 (sentinel group) - Placebo<br>Single dose of Placebo for TBI-223 50 mg (n=1) dosed at least 24 hours before the Cohort 1 (remainder of cohort). | Drug: Placebo for TBI-223 50mg<br>* Matching placebo for TBI-223 50mg supplied for oral administration.<br>|
| Active Comparator: Cohort 1 (remainder of cohort) - Active<br>Single dose of TBI-223 50 mg (n=4). | Drug: TBI-223 50mg<br>* TBI-223 50 mg supplied for oral administration.<br>|
| Placebo Comparator: Cohort 1 (remainder of cohort) - Placebo<br>Single dose of Placebo for TBI-223 50 mg (n=1). | Drug: Placebo for TBI-223 50mg<br>* Matching placebo for TBI-223 50mg supplied for oral administration.<br>|
| Active Comparator: Cohort 2 - Cohort 7 - Active<br>Single dose of TBI-223 100, 300, 600, 1200, 2000, 2600 mg; n=3 per dosing group. | Drug: TBI-223 100, 300, 600, 1200, 2000, 2600 mg<br>* TBI-223 100, 300, 600, 1200, 2000, 2600 mg supplied for oral administration.<br>|
| Placebo Comparator: Cohort 2 - Cohort 7 - Placebo<br>Single dose of matching Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg, n=1 per dosing group. | Drug: Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg<br>* Matching placebo for 100, 300, 600, 1200, 2000, 2600 mg TBI-223 supplied for oral administration.<br>|
| Active Comparator: Cohort 3b - Active - Oral Capsule<br>Single dose of 300 mg in oral enteric capsule, n=4 per dosing group. | Drug: TBI-223 300 mg capsule<br>* TBI-223 300 mg capsule supplied for oral administration<br>|
| Placebo Comparator: Cohort 3b - Placebo - Oral Capsule<br>Single dose of placebo for 300 mg in oral enteric capsule, n=1 per dosing group. | Drug: Placebo for TBI-223 300 mg capsule<br>* Placebo for TBI-223 300 mg capsule supplied for oral administration<br>|
| Active Comparator: Cohort 8 - Prototype Tablet 1<br>Single dose of TBI-223 sustained-release (SR) tablet prototype 1, 3 x 600 mg, n=6 per cohort. | Drug: TBI-223 Prototype 1 SR Tablet<br>* Prototype 1 TBI-223 600 mg sustained-release (SR) tablet<br>|
| Active Comparator: Cohort 8 - Prototype Tablet 2<br>Single dose of TBI-223 SR tablet prototype 2, 3 x 600 mg, n=6 per cohort. | Drug: TBI-223 Prototype 2 SR Tablet<br>* Prototype 2 TBI-223 600 mg SR tablet<br>|
| Active Comparator: Cohort 8 - Prototype Tablet 3<br>Single dose of TBI-223 SR tablet prototype 3, 2 x 900 mg, n=6 per cohort. | Drug: TBI-223 Prototype 3 SR Tablet<br>* Prototype 3 TBI-223 900 mg SR tablet<br>|
| Active Comparator: Cohort 8 - IR Tablet fasted<br>Single dose of TBI-223 immediate-release (IR) tablet prototype 4, 2 x 1000 mg, n=6 per cohort; fasted prior to dose. | Drug: TBI-223 IR Tablet<br>* TBI-223 1000 mg immediate release (IR) tablet<br>|
| Active Comparator: Cohort 9 - IR Tablet with meal<br>Single dose of TBI-223 immediate-release (IR) tablet, 2 x 1000 mg, n=6 per cohort; fed prior to dose. | Drug: TBI-223 IR Tablet<br>* TBI-223 1000 mg immediate release (IR) tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related and other adverse events as assessed by the Division of Microbiology and Infectious Disease (DMID) Toxicity Table | Safety assessments will include physical and detailed neurological examinations (including assessments of mental status, cranial nerves, motor system, sensory system, reflexes, coordination and gait), vital signs including heart rate and respiratory rate, ECGs, cardiac monitor (Holter monitoring starting 24 hours prior to dose and continuing for 48 hours post dose), collection of all AEs (including treatment- related AEs and SAEs) and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis prior to dosing and at protocol defined time points up to 72 hours post dose). Subjects will be called 11 days post dose to query for AEs. | Day 1 - Day 4 Post Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUClast | AUClast will be calculated from plasma concentrations of TBI-223 and M2. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUCinf | AUCinf will be calculated from plasma concentrations of TBI-223 and M2. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Cmax | Cmax will be calculated from plasma concentrations of TBI-223 and M2. Cmax is maximum concentration, determined directly from individual concentration-time data. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Tmax | Tmax will be calculated from plasma concentrations of TBI-223 and M2. Tmax is time of the maximum concentration. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using CL/F | CL/F will be calculated from plasma concentrations of TBI-223 only. CL/F is apparent total clearance after single administration. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using Vz/F | Vz/F will be calculated from plasma concentrations of TBI-223 only. Vz/F is apparent volume of distribution in the terminal phase. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using λz | λz will be calculated from plasma concentrations of TBI-223 and M2. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile. | Day 1 - Day 2 | 
| Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using T1/2 | T1/2 will be calculated from plasma concentrations of TBI-223 and M2. T½ or t½ is the observed terminal half-life. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using AUClast, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | AUClast will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using AUCinf, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | AUCinf will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using Cmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | Cmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Cmax is maximum concentration, determined directly from individual concentration-time data. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using Tmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | Tmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Tmax is time of the maximum concentration. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using CL/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | CL/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. CL/F is apparent total clearance after single administration. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using Vz/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | Vz/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Vz/F is apparent volume of distribution in the terminal phase. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using λz, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | λz will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile. | Day 1 - Day 2 | 
| Compare the rate and extent of absorption of a single dose of TBI-223 using T1/2, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects | T1/2 will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. T½ or t½ is the observed terminal half-life. | Day 1 - Day 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB, Tuberculosis, TBI-223, Pulmonary Tuberculosis