Safety of Intravenous Apramycin in Adults

NCT05590728 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 20-0012
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

A Phase I, open label study of a single dose of 30 mg/kg of apramycin administered intravenously (IV) over 30 (+/- 5) minutes. Twenty subjects will be enrolled in the study to one of 5 cohorts, T1-T5, each corresponding to a timepoint after initiation of infusion at which a single fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) is performed. There will be 4 subjects per cohort. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4. Enrollment and dosing will be determined by bronchoscopy schedule. For each cohort, if 2 subjects are scheduled to receive study drug on the same day, the dose will be administered sequentially at least 2 hours apart. The primary objective is to assess plasma pharmacokinetic (PK) profile of apramycin and lung penetration of apramycin in epithelial lining fluid (ELF) and alveolar macrophages (AM) after single intravenous (IV) apramycin dose of 30 mg/kg in healthy subjects.

Conditions

Bacterial Infection

Keywords

Apramycin; Lung Pharmacokinetics; Open-label; Phase I; Respiratory

Outcome Measures

Primary Outcomes (15)

• Area Under the Concentration-time Curve From Time Zero to 8 h (AUC 0-8) of Total Apramycin in Epithelial Lining Fluid (ELF) and Alveolar Macrophage (AM)

  AUC 0-8 (ug\*h/mL) was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the geometric mean (GM) concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants.

  0 h through 8 h post dose

• Area Under the Concentration-time Curve From Time Zero to Infinity (AUC 0-inf) of Total Apramycin in ELF and AM

  AUC 0-inf (ug\*h/mL) was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the geometric mean (GM) concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants.

  0 h through 8 h post dose

• Maximum Concentration (Cmax) of Total Apramycin in ELF and AM

  Cmax (ug/mL) was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the geometric mean (GM) concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants.

  0 h though 8 h post dose

• Time of Maximum Concentration (Tmax) of Total Apramycin in ELF and AM

  Tmax (h) was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the geometric mean (GM) concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants.

  0 h through 8 h post dose

• Terminal Elimination Half-Life (t1/2) of Total Apramycin in ELF and AM

  t1/2 (h) was estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the geometric mean (GM) concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants.

  0 h through 8 h post dose

• Area Under the Concentration-time Curve From Time Zero to 8 h (AUC 0-8) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of AUC 0-8 (h\*ug/mL). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study.

  0 h through 8 h post dose

• Area Under the Concentration-time Curve From Time Zero to 24 h (AUC 0-24) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of AUC 0-24 (h\*ug/mL). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study.

  0 h through 24 h post dose

• Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration Above the Lower Limit of Quantitation (AUC 0-last) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of AUC (0-last) (h\*µg/mL). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study.

  0 h through 60 h post dose

• Area Under the Concentration-time Curve From Time Zero to Infinity (AUC 0-inf) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of AUC (0-Inf) (h\*µg/mL). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study. AUC 0-Inf was estimated for plasma concentration data with the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) = 0.90 and includes at least 3 timepoints after time to maximum concentration (Tmax).

  0 h through 60 h post dose

• Maximum Concentration (Cmax) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of Cmax (ug/mL). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study.

  0 h though 60 h post dose

• Time of Maximum Concentration (Tmax) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of Tmax (h). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study.

  0 h through 60 h post dose

• Terminal Elimination Half-Life (t1/2) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of t1/2 (h). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study. t1/2 was estimated for plasma concentration data with the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) = 0.90 and includes at least 3 timepoints after time to maximum concentration (Tmax).

  0 h through 60 h post dose

• Central Volume of Distribution (Vd) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of Vd (L/kg). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study. Vd was estimated for plasma concentration data with the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) = 0.90 and includes at least 3 timepoints after time to maximum concentration (Tmax).

  0 h to 60 h post dose

• Total Clearance (CLT) of Total Apramycin in Plasma

  Geometric mean (GM) and coefficient of variation as a percent (CV%) of CLT (L/h/kg). PK parameters were estimated from the total apramycin plasma concentration-time data after a complete dose using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MC/MS bioanalytical assay for plasma samples collected during the study. CLT was estimated for plasma concentration data with the following lambda-z acceptance criteria: rsq\_adjusted (adjusted r squared) = 0.90 and includes at least 3 timepoints after time to maximum concentration (Tmax).

  0 h through 60 h post dose

• Ratio of ELF to Plasma and AM to Plasma Apramycin Exposure Parameters

  The ratios for Cmax (ug/mL), AUC 0-8 (ug\*h/mL), and AUC 0-inf (ug\*h/mL) of ELF to plasma and AM to plasma were calculated by dividing the Cmax (ug/mL), AUC 0-8 (ug\*h/mL), and AUC 0-inf (ug\*h/mL) of ELF and AM by the Cmax (ug/mL), AUC 0-8 (ug\*h/mL), and AUC 0-inf (ug\*h/mL) of total apramycin in plasma, respectively. All PK parameters were estimated using Phoenix WinNonlin Non-compartmental analysis. Each participant only contributed one ELF and AM concentration at one time point, so the PK parameters for ELF and AM were calculated using the GM concentration at each BAL sampling time point, resulting in a single parameter estimate of ELF and AM across all participants. The PK parameters for total apramycin in plasma were calculated using the GM result of the total apramycin in plasma concentrations at the corresponding BAL time point.

  0 h through 8 h post dose

Secondary Outcomes (10)

• Frequency of Serious Adverse Events (SAEs)

  Day 1 through Day 30

• Frequency of Treatment-emergent Adverse Events (TEAEs)

  Day 1 through Day 30

• Frequency of Abnormal Physical Exam Findings

  Day 1 through Day 14

• Frequency of Abnormal Vital Sign Findings

  Day 1 through Day 14

• Frequency of Abnormal Chemistry Lab Measurements

  Day 1 through Day 14

Study Arms (5)

T1

EXPERIMENTAL

Subjects 18 to 45 years of age to receive 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 0.5 h (+/- 5 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4

Drug: Apramycin (EBL-1003)

T2

EXPERIMENTAL

Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 2 h (+/- 5 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4

Drug: Apramycin (EBL-1003)

T3

EXPERIMENTAL

Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 4 h (+/-10 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4

Drug: Apramycin (EBL-1003)

T4

EXPERIMENTAL

Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. 8 h (+/- 15 min) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4

Drug: Apramycin (EBL-1003)

T5

EXPERIMENTAL

Subjects 18 to 45 years of age to receive single 30 mg/kg apramycin dose administered intravenously (IV) in a forearm vein over 30 min (+/- 5 min) using a syringe or infusion pump. Cohort T5 will be enrolled after plasma and lung apramycin concentrations and preliminary PK data analysis are completed in cohorts T1-T4 24 h (+/- 1 h) after dosing a single bronchoscopy with bronchoalveolar lavage (BAL) will be performed to analyze concentration of apramycin in BAL. N=4

Drug: Apramycin (EBL-1003)

Interventions

Apramycin (EBL-1003) DRUG

A mono-substituted 2-deoxystreptamine comprising a unique bicyclic octadiose moiety. It is a crystalline free base of the amoniglycoside apramycin.

T1; T2; T3; T4; T5

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject reads and signs the Informed Consent Form (ICF) and agree to have bronchoscopy with bronchoalveolar lavage under sedation or light anesthesia and comply with study procedures.
• Healthy male or non-pregnant, non-lactating female subjects 18 to 45 years of age (both inclusive) at the time of dosing.
• \*Note 1: Determined by medical history (MH), medication use, physical examination (PE), and vital signs, clinical laboratory tests and 12-lead ECG within reference ranges at Screening and Day-2. (See Sections 8.1 and 8.2; and Appendix B, Table 2, Table 3 and Table 4 and the study-specific MOP.)
• Exceptions to BP, HR and laboratory test values being with normal ranges are:
• Abnormal HR and BP on first measurement may be repeated twice more with the subject resting between measurements for at least 5 min according to Section 8.1.6.
• Subjects with baseline HR \>/= 45 to 50 bpm may be accepted if otherwise healthy adults with known history of asymptomatic bradycardia.
• Subjects with baseline SBP up to 140 mmHg and DBP up to 90 mmHg may be accepted if otherwise healthy.
• A laboratory value that is Grade 1 will be allowed if not considered to be clinically significant by the investigator, with the exception of ALT, AST, AP, BUN, urine protein, serum creatinine or estimated glomerular filtration rate (eGFR) \<70 mL/min /1.73 m\^2 by the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation.
• Female subjects of childbearing potential should use highly effective methods of contraception from the time of screening to 30 days after dosing.
• Note 1: A female is considered of childbearing potential unless post-menopausal (defined as history of \>/=1 year of spontaneous amenorrhea and a FSH level \>40 IU/L), or permanently surgically sterilized.
• Note 2: Highly effective contraceptive methods include: (a) surgical sterilization methods, such as tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful tubal obliteration (e.g., Essure(R)) with documented radiological confirmation test at least 90 days after the procedure, or (b) long-acting reversible contraception, such as progestin-releasing subdermal implants, copper intrauterine devices (IUDs), levonorgestrel-releasing IUDs.
• Note 3: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented.
• Males, including vasectomized men, having sexual intercourse with women of childbearing potential must agree to consistent use of condoms from IMP administration through at least 30 days after dosing, and must also agree to not donate sperm during this same time period.
• \*Note: A subject who is not sexually active and abstains from sexual intercourse can be enrolled and abstinence documented.
• BMI 18.0 to 32.0 kg/m\^2 (inclusive) and body weight not less than 50 kg.

You may not qualify if:

• All must be answered NO for the subject to be eligible for study participation:
• Lactating females.
• Medical and surgical history:
• Any history of hypersensitivity to aminoglycosides.
• Any history of drug hypersensitivity, asthma, urticaria or other severe allergic diathesis.
• Any history of seasonal allergies with ongoing symptoms for more than a week prior to dosing requiring glucocorticoids and/or frequent use of antihistamines for treatment.
• Any history of a chronic condition that may increase risk to subject or interfere with endpoint assessment, or any unstable chronic disease.
• Note 1: Unstable chronic disease is defined by need for frequent medical interventions that lead to a change in medications and/or required hospitalization, surgery or an invasive procedure or emergency department/urgent care visit.
• Note 2: Any chronic disease, that has been diagnosed within 90 days of screening is excluded.
• History of any psychiatric medical condition that has required hospitalization in the last 5 years or subject is considered psychologically unstable by the investigator.
• History of acute or chronic problems with hearing and/or balance in the last 24 months.
• Note: These include but not limited to use of hearing aid, head injury leading to otologic damage, tumor of the head or neck, autoimmune disease of the inner ear, tinnitus, vestibular disease, auditory neurinoma, endolymphatic hydrops and/or Meniere's disease, perilymphatic fistula, otitis media, labyrinthitis, sudden hearing loss, known retrocochlear hearing impairment, conductive hearing loss exceeding 10 dB at any frequency, ear canal and/or middle ear disease including inflammation or effusion, pathological tympanometry.
• Past injury or surgery to the middle or inner ears.
• Note: Myringotomy or tympanic tube insertion in childhood with complete healing and normal hearing test are excluded.
• Family history of hearing loss before the age of 60.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Alliance for Multispecialty Research, LLC - Knoxville

Knoxville, Tennessee, 37920, United States

Location

MeSH Terms

Conditions

Bacterial Infections

Interventions

apramycin

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: George A. Saviolakis, MD, PhD
• Organization: DynPort Vaccine Company, a GDIT Company

George.Saviolakis@gdit.com

301-835-4101

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2022
• First Posted: October 21, 2022
• Study Start: June 16, 2023
• Primary Completion: October 22, 2023
• Study Completion: October 22, 2023
• Last Updated: March 6, 2025
• Results First Posted: December 10, 2024

Record last verified: 2022-10-17

Locations

US (1)