Absorption, Elimination and Safety of 14C-labeled Radioactive BTZ-043, a New Compound in TB Treatment

Study Overview
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Brief Summary
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This study is a Phase 1, single-center, open-label study to investigate the absorption, metabolism, and excretion of BTZ-043 after a single oral administration of 500 mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043 in 4 healthy adult male subjects

Detailed Description
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A total of 4 evaluable subjects completing all procedures are required. Six (6) subjects will be enrolled in the cohort in order to have 4 evaluable subjects. The study will consist of a screening period (Day -21 to -2), a baseline period (Day -1), a single dose treatment on Day 1 with a minimum of 96 hours (=4 days) post dose in-house observation period (Days -1 up to afternoon Day 5), and a follow-up visit 30 days (±2 days) after the [14C]BTZ-043 dose. Subjects will be administered a single 500 mg [14C]BTZ-043 dose as drinking suspension. Subjects will be confined to the clinical site for at least 96 hours following drug administration (ie, afternoon of Day 5). During this time, blood, feces, and urine samples for measurement of [14C]BTZ-043 and metabolites will be collected. The subjects will be released from the clinic approximately 96 hours to 168 hours after dose administration and upon satisfactory recovery of radioactivity (at least 90%) approved by the Sponsor's scientific advisor after consulation of the Sponsor.

Official Title
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A Single-Center, Open Label Study to Investigate the Mass Balance, Excretion Pathways and Metabolites After a Single Oral Dose of 500 MG, 3.7 MBq, [14C]BTZ-043 in Healthy Male Volunteers

Conditions
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Tuberculosis, Tuberculosis, Pulmonary, Bacterial Infections Respiratory, Lung Diseases, Mycobacterium Infections

Intervention / Treatment
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* Drug: 500mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sex : male Age : 18 years to 55 years, inclusive, at screening. Body mass index (BMI) : 18.0 to 29.0 kg/m2, inclusive, at screening. Weight : 55 to 90 kg, inclusive, at screening. Status : healthy subjects. Male subjects, if not surgically sterilized, must agree to use adequate contraception and not donate sperm from admission to the clinical research center until 90 days after the follow-up visit. Adequate contraception for the male subject (and his female partner, if she is of childbearing potential) is defined as using hormonal contraceptives or an intrauterine device combined with at least 1 of the following forms of contraception: a diaphragm, a cervical cap, or a condom. Total abstinence, in accordance with the lifestyle of the subject, is also acceptable. All prescribed medication must have been stopped at least 30 days prior to admission to the clinical research center. All over-the-counter medications, vitamin preparations (especially vitamin C), other food supplements, and herbal medications (eg, St. John's wort) must have been stopped at least 14 days prior to admission to the clinical research center. An exception is made for paracetamol, which is allowed up to 48 hours prior to study drug administration. No vaccination within 14 days prior to study drug administration. Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to screening and admission to the clinical research center. Ability and willingness to abstain from methylxanthine-containing beverages or food (coffee, tea, cola, chocolate, and energy drinks), grapefruit (juice), corn (whole corn kernels and popcorn), cruciferous vegetables, and bitter oranges from 48 hours (2 days) prior to admission to the clinical research center. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory, ECG, and vital signs, as judged by the Investigator. Willing and able to sign the ICF. Exclusion Criteria: Participation in another study with a radiation burden of >0.1 mSv and ≤1 mSv in the period of 1 year prior to screening; a radiation burden of >1.1 mSv and ≤2 mSv in the period of 2 years prior to screening; a radiation burden of >2.1 mSv and ≤3 mSv in the period of 3 years prior to screening, etc. Exposure to radiation for diagnostic reasons (except dental X-rays and plain X-rays of thorax and bony skeleton [excluding spinal column]), or during work within 1 year prior to drug administration. Irregular defecation pattern (less than once per day on average). Employee of PRA, Nuvisan, or the Sponsor. History of relevant drug and/or food allergies. Using tobacco products within 60 days prior to drug administration. History of alcohol abuse or drug addiction (including soft drugs like cannabis products). Positive drug and alcohol screen (opiates, methadone, cocaine, amphetamines [including ecstasy], cannabinoids, barbiturates, benzodiazepines, gamma-hydroxybutyric acid, tricyclic antidepressants, and alcohol) at screening or admission to the clinical research center. Average intake of more than 24 grams of alcohol per day. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, or HIV 1 and 2 antibodies. Participation in a drug study within 30 days prior to drug administration in the current study. Participation in more than 4 drug studies in the 12 months prior to drug administration in the current study. Donation or loss of more than 450 mL of blood within 60 days prior to drug administration. Donation or loss of more than 1.5 liters of blood in the 10 months prior to drug administration in the current study. Significant and/or acute illness within 5 days prior to drug administration that may impact safety assessments, in the opinion of the Investigator. Unwillingness to consume the Food and Drug Administration (FDA)-recommended high-fat breakfast. Unsuitable veins for infusion or blood sampling. Positive nasopharyngeal PCR test for SARS-CoV-2 on Day -1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single oral administration of 500 mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043<br>4 subjects to receive a single oral administration of 14C-labeled radioactive 500mg BTZ-043 | Drug: 500mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043<br>* Single oral administration of 14C-labeled radioactive 500mg BTZ-043<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of total radioactivity | Total radioactivity concentrations in plasma | Day 1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Time to attain maximum observed plasma concentration (tmax) of total radioactivity | Time to maximum total radioactivity concentrations in plasma | Day 1 to Day 5. | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of total radioactivity | Area under the plasma concentration-time curve up to time t, where t is the last point with concentrations above the lower limit of quantification | Day 1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of total radioactivity | Calculated as: AUC0-inf=AUC0-t+Clast/kel,where Clast is the last measurable plasma concentration | Day 1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Terminal elimination rate constant (Kel) of total radioactivity | Fraction that is eliminated from the body during a given period of time | Day 1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Terminal elimination half-life (t1/2) of total radioactivity |  | Day 1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Cumulative amount excreted in urine (Ae urine) of total radioactivity |  | Urine collection Day -1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Cumulative amount of total radioactivity excreted in feces (Ae feces) |  | Feces collection Day -2 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Cumulative amount of total radioactivity excreted in vomit, if produced (Ae vomit) | If produced, vomit will be collected up to 8 hours after the administration of the study drug for total radioactivity determination. | Collection up to 8 hours after the administration of the study drug | 
| Total amount of total radioactivity excreted (Ae total) | Calculated as Aetotal=Aeurine+Aefeces(+Aevomit) | Day -2 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Fraction of the total radioactivity administered excreted in urine (%) (Fe urine) of total radioactivity |  | Urine collection Day -1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Fraction of the total radioactivity administered excreted in feces (%) (Fe feces) |  | Feces collection Day -2 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Fraction of the total radioactivity administered excreted in vomit(%) (Fe vomit) |  | If produced, vomit will be collected up to 8 hours after the administration of the study drug for total radioactivity determination. | 
| Fraction of the total radioactivity administered (Fe total) excreted in urine, feces, and vomit (if produced) (%) |  | Urine collection Day -1 to Day 5. Feces collection Day -2 to Day 5. If produced, vomit will be collected up to 8 hours after the administration of the study drug for total radioactivity determination. | 
| Maximum Observed Plasma Concentration (Cmax) of BTZ-043 and main metabolites | Total concentrations of BTZ-043 and main metabolites in plasma | Day 1 to Day 3. | 
| Time to attain maximum observed plasma concentration (tmax) of BTZ-043 and main metabolites | Time to maximum concentrations of BTZ-043 and main metabolites in plasma | Day 1 to Day 3. | 
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUC0-t) of BTZ-043 and main metabolites | Area under the plasma concentration-time curve up to time t, where t is the last point with concentrations above the lower limit of quantification | Day 1 to Day 3. | 
| Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of BTZ-043 and main metabolites | Calculated as: AUC0-inf=AUC0-t+Clast/kel,where Clast is the last measurable plasma concentration | Day 1 to Day 3. | 
| Terminal elimination half-life of total radioactivity (t1/2) of BTZ-043 and main metabolites |  | Day 1 to Day 3. | 
| Terminal elimination rate constant (Kel) of BTZ-043 and main metabolites | Fraction that is eliminated from the body during a given period of time | Day 1 to Day 3. | 
| Fraction of the dose administered excreted in urine (%) (Fe urine) of BTZ-043 and main metabolites |  | Urine collection Day -1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Cumulative amount excreted in urine (Ae urine) of BTZ-043 and main metabolites |  | Urine collection Day -1 to Day 5. Further timepoints possible up to total recovery of radioactivity. | 
| Apparent oral clearance (CL/F) of BTZ-043 | Calculated as dose/AUC0-inf. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. | Day 1 to Day 3. | 
| Apparent volume of distribution (Vz/F) at terminal phase of BTZ-043 | The theoretical volume in which the a drug would need to be distributed to produce a desired plasma concentration. Apparent volume of distribution after oral dose is influenced by the fraction absorbed. | Day 1 to Day 3. | 
| Renal clearance (CL r) of BTZ-043 | Hypothetical volume of plasma from which a substance is completely removed per unit time. Using noncompartmental analysis. | Day 1 to Day 3. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events oncerning safety laboratory graded using the most current version of the MedDRA: | Laboratory tests: Clinical laboratory tests including clinical chemistry, hematology, and urinalysis | At screening, on Day -1 (admission), Day 2, and Day 4; and at follow-up. | 
| Number of participants with treatment-related adverse events concerning vital signs graded using the most current version of the MedDRA: | Supine systolic and diastolic blood pressure, pulse, body temperature, and respiratory rate: at screening; at admission; at predose and at 1 hour, 4 hours, and 24 hours postdose; at discharge; and at follow-up. | At screening, on Day -1 (admission), Day 2, and Day 4; and at follow-up. | 
| Number of participants with treatment-related adverse events concerning physical examination graded using the most current version of the MedDRA: | Complete physical examinations will be conducted, Symptom driven physical examinations may be conducted at any time, per the Investigator's discretion. | At Screening, Day -1, and follow-up/early termination | 
| Number of participants with treatment-related adverse events concerning 12-lead electrocardiogram graded using the most current version of the MedDRA: | 12-lead ECG | At screening; Day -1, and 1 hour, 4 hours, and 24 hours postdose; at discharge; and at follow-up. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Bacterial Agents