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

NCT04874948 | Completed Phase 1 Results

• 1 other identifier: LMU-IMPH-BTZ-043-03
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

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

Keywords

Anti-Bacterial Agents

Outcome Measures

Primary Outcomes (9)

• Rates and Routes of Excretion

  To determine the rates and routes of excretion of \[14C\]BTZ-043-related radioactivity, including mass balance of total drug-related radioactivity in urine and feces (and vomit, if applicable), following the oral administration of a single 500 mg dose of \[14C\]BTZ-043 in healthy male volunteers. All excreta were collected for the analysis for 14C quick or normal counts of total radioactivity (as feasible). the radioactivity measured was translated into mg eq (Radioactivity equivalent to 1 mg BTZ-043).

  Urine and faeces were collected from the administration of the study medication until cumulative excretion reached 90% of total radioactivity administered. This was achieved by all subjects after 168 hours.

• Pharmacokinetics of Total Radioactivity in Blood and Plasma (Cmax)

  To determine the pharmacokinetics (PK) of total radioactivity in whole blood and in plasma. Measured radioactivity was translated into ng equivalent of BTZ-043. Based on the ng eq, pharmacokinetic parameters were calculated.

  Blood samples for total radioactivity were collected from day 1 until 168 h post dosing

• Pharmacokinetics of Total Radioactivity in Blood and Plasma (AUC-t)

  To determine the pharmacokinetics (PK) of total radioactivity in whole blood and in plasma. Measured radioactivity was translated into ng equivalent of BTZ-043. Based on the ng eq, pharmacokinetic parameters were calculated.

  Blood samples for total radioactivity were collected from day 1 until 168 h post dosing

• Pharmacokinetics of Total Radioactivity in Blood (T1/2)

  To determine the pharmacokinetics (PK) of total radioactivity in whole blood and in plasma. Measured radioactivity was translated into ng equivalent of BTZ-043. Based on the ng eq, pharmacokinetic parameters were calculated.

  Blood samples for total radioactivity were collected from day 1 until 168 h post dosing

• Pharmacokinetics of Total Radioactivity in Plasma (T1/2)

  To determine the pharmacokinetics (PK) of total radioactivity in whole blood and in plasma. Measured radioactivity was translated into ng equivalent of BTZ-043. Based on the ng eq, pharmacokinetic parameters were calculated.

  Blood samples for total radioactivity were collected from day 1 until 168 h post dosing

• Plasma PK of BTZ-043 and Main Metabolites (Cmax)

  To characterize the plasma PK of BTZ-043 and main metabolites by liquid chromatography-mass spectrometry (LC-MS), if applicable. BTZ-043 is metabolized in the human body. Some of the metabolites were known prior to this study like the main metabolite M2, a hydrid Meisenheimer complex or the aminometabolite M1. Metabolite M4 and M10 were known before as well, therefore, the bioanalytical methods mentioned above could be developed and validated for these metabolites.Pharmacokinetic parameters are calculated from the individual plasma level measurements.

  Day 1 to Day 3

• Plasma PK of BTZ-043 and Main Metabolites (AUC-last)

  To characterize the plasma PK of BTZ-043 and main metabolites by liquid chromatography-mass spectrometry (LC-MS), if applicable. BTZ-043 is metabolized in the human body. Some of the metabolites were known prior to this study like the main metabolite M2, a hydrid Meisenheimer complex or the aminometabolite M1. Metabolite M4 and M10 were known before as well, therefore, the bioanalytical methods mentioned above could be developed and validated for these metabolites. Pharmacokinetic parameters are calculated from the individual plasma level measurements.

  Day 1 to Day 3

• Plasma PK of BTZ-043 and Main Metabolites (t1/2)

  To characterize the plasma PK of BTZ-043 and main metabolites by liquid chromatography-mass spectrometry (LC-MS), if applicable. BTZ-043 is metabolized in the human body. Some of the metabolites were known prior to this study like the main metabolite M2, a hydrid Meisenheimer complex or the aminometabolite M1. Metabolite M4 and M10 were known before as well, therefore, the bioanalytical methods mentioned above could be developed and validated for these metabolites. Pharmacokinetic parameters are calculated from the individual plasma level measurements.

  Day 1 to Day 3

• Urine Concentrations of BTZ-043 and Main Metabolites

  Urine volume was measured after every micturation and hamilton pools have been prepared for analysis of BTZ-043 and main metabolites by LC-MS. BTZ-043 could only be measured in urine within the first 24h, then no additional BTZ-043 was excreted in urine anymore. The same applies for M1. M2, M4 total and M10 total excretion could be measured in urine up to 48h post dose.

  Assessed from time of dosing up to 168 h post dose. BTZ-043 and metabolites were excreted fom 0 - 24 h (BTZ-043 and M1) and from 0 - 48 h (M2, M4 total and M10 total).

Secondary Outcomes (1)

• Number of Adverse Events

  Day -1 to day 32

Study Arms (1)

Single oral administration of 500 mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043

EXPERIMENTAL

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

Interventions

500mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043 DRUG

Single oral administration of 14C-labeled radioactive 500mg BTZ-043

Single oral administration of 500 mg BTZ-043 containing 3.7 MBq of [14C]BTZ-043

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Michael Hoelscher: lead
• Leibniz Institute for Natural Product Research and Infection Biology Hans Knöll Institute: collaborator

Study Sites (1)

PRA Health Sciences (PRA) - Early Development Services (EDS)

Groningen, Netherlands

Location

MeSH Terms

Conditions

Tuberculosis; Tuberculosis, Pulmonary; Lung Diseases; Mycobacterium Infections

Condition Hierarchy (Ancestors)

Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Respiratory Tract Diseases

Results Point of Contact

• Title: Dr. med. vet. Julia Dreisbach
• Organization: Klinikum der Universität München (LMU)

julia.dreisbach@med.uni-muenchen.de

+49 89 4400

Study Officials

• Jan Jaap van Lier, MD

  PRA Health Sciences (PRA) - Early Development Services (EDS)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: April 22, 2021
• First Posted: May 6, 2021
• Study Start: October 8, 2021
• Primary Completion: October 15, 2021
• Study Completion: November 9, 2021
• Last Updated: December 31, 2024
• Results First Posted: December 5, 2024

Record last verified: 2024-12

Locations

NL (1)