Intravenous Fosfomycin Pharmacokinetics Study

NCT03910673 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 16-0058HHSN272201300017I
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1, open-label, multiple-dose trial conducted at a single center. The treatment period will consist of three 6 g doses (18 g) of ZTI-01 as a 1-hour intravenous (IV) infusion (+10 minute window). A total of 30 enrolled subjects will be randomized to undergo a single standardized bronchoscopy with bronchoalveolar lavage (BAL) at one of five sampling times. A total of 6 subjects will be assigned to each BAL-sampling time. Up to ten additional enrolled subjects will act as alternates to obtain 30 evaluable subjects. An evaluable subject is defined as a subject who receives all doses of ZTI-01, undergoes BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and undergoes at least the one blood sampling timepoint that is concurrent with the assigned BAL sampling timepoint, with blood sampling volume that is adequate for testing. The objectives of the study are to assess safety and pharmacokinetics (PK) for a multiple dose regimen of IV-infused ZTI-01.

Conditions

Bacterial Infection; Multiple-drug Resistance; Pathogen Resistance

Keywords

Adults; Fosfomycin Disodium; Healthy; Intrapulmonary; Intravenous; Pharmacokinetics; Phase 1; ZTI-01

Outcome Measures

Primary Outcomes (16)

• Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01

  Mean and standard deviation (SD) of the AUC 0-8 (h\*ug/mL) and AUC 0-inf (h\*ug/mL). PK parameters were estimated from the ZTI-01 plasma concentration-time data after Dose 1 (Day 1) and Dose 3 (Day 2) using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study. AUC 0-8 was estimated for the plasma concentration data after Dose 1 and Dose 3. AUC 0-inf was estimated for the plasma concentration data after Dose 3 with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax).

  Day 1 to Day 2

• Clearance (CL) of ZTI-01

  Mean and SD of the clearance (CL) of ZTI-01 (L/h). The clearance PK parameter was estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for plasma samples collected during the study. If the amount extrapolated portion of AUC 0-inf was \>20%, the estimated CL value was excluded from statistical summaries of the parameter estimates.

  Day 2

• Intrapulmonary Pharmacokinetics of ZTI-01

  Intrapulmonary pharmacokinetics of ZTI-01 was defined as the percent penetration of lung epithelial lining fluid (ELF) and alveolar macrophages (AMs). The estimate of the percent lung penetration was calculated by dividing the AUC 0-8 of ELF and AM by the AUC 0-8 of plasma fosfomycin. The AUC 0-8 of ELF and AM was calculated using the median result at each BAL sampling timepoint, resulting in a single AUC 0-8 of ELF and AM across all subjects. The AUC 0-8 of plasma fosfomycin was calculated using the median result of the plasma fosfomycin concentrations at the corresponding BAL timepoint.

  Day 2

• Maximum Measured Plasma Concentration (Cmax) of ZTI-01

  Mean and standard deviation (SD) of the Cmax (ug/mL) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 1 and Dose 3 using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments

  Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical chemistry assessments with toxicity grading and associated thresholds include sodium \<135 mEq/L or \>145 mEq/L, potassium \<3.5 mEq/L or \>5.0 mEq/L, random glucose \<=69 mg/dL or \>=141 mg/dL, blood urea nitrogen (BUN) \>=21 mg/dL, creatinine \>1.0 mg/dL (Females) or \>1.3 mg/dL (Males), calcium \<8.7 mg/dL or \>10.2 mg/dL, magnesium \<=1.7 mg/dL, phosphorous \<=2.2 mg/dL, creatine phosphokinase (CPK) \>=221 mg/dL, albumin \>=2.8 g/dL, total protein \<5.8 g/dL, alkaline phosphatase (ALP) \>=111 U/L, aspartate aminotransferase (AST) \>=42 U/L, alanine aminotransferase (ALT) \>54 U/L (Females) or \>63 (Males) U/L, total bilirubin \>=1.6 mg/dL, direct bilirubin \>=0.7 mg/dL, total cholesterol \>=301 mg/dL, triglycerides \>500 mg/dL, and lactate dehydrogenase (LDH) \>200 U/L.

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments

  Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical hematology assessments with toxicity grading and associated threshold include hemoglobin \<=11.9 g/dL (Females) or \<= 13.6 g/dL (Males), white blood cell count \<=3.1 10\^9/L or \>=9.9 10\^9/L, lymphocytes \<0.6 10\^9/L, neutrophils \<2.0 10\^9/L, eosinophils \>0.7 10\^9/L, and platelets \<=149 10\^9/L.

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments

  Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical coagulation assessments with toxicity grading and associated threshold include prothrombin time (PT) \>13.1 seconds and activated partial thromboplastic time (aPTT) \>37.1 seconds.

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments

  Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical urinalysis assessments with toxicity grading and associated threshold include protein \>= 1+, glucose \>= 1+, and red blood cell (RBC) count from microscopy \>= 5 rbc/hpf.

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Physical Examination Findings

  Physical exams included assessment of skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, musculoskeletal system/extremities, abdomen, nervous system, weight, height, and body mass index (BMI).

  Day 1 to Day 2

• Number of Participants Experiencing Abnormal Vital Sign Measurements

  Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign measurements with toxicity grading and associated threshold include systolic blood pressure (BP) \>=141 mmHg or \<=89 mmHg; diastolic BP \>=91 mmHg; heart rate \>=101 beats per minute (bpm) and \>25% change from baseline or \<=54 bpm (if baseline \>=60 bpm) or \<=49 bpm (if baseline \<60 bpm); respiratory rate \>=23 breaths per minute; and temperature \>=38.0 degrees Celsius.

  Day 1 to Day 2

• Number of Participants Experiencing Adverse Events (AEs)

  The number of participants who experienced at least one unsolicited treatment emergent AE (TEAE) of any severity and relatedness by MedDRA System Organ Class (SOC). AEs included local and systemic reactions. Any medical condition that was present at screening was considered as a baseline finding and not reported as an AE. However, if its Grade increased at any time during the trial such that it met the AE definition, it was recorded as an AE.

  Day 1 to Day 3

• Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings

  Each subject is only counted once per toxicity grade for the worst severity recorded. ECG assessments with toxicity grading and associated threshold include QTc Interval \>=450 msec, PR Interval \>=200 msec and \>25% change from baseline, and QRS Interval \>=120 msec and \>25% change from baseline.

  Day 1 to Day 2

• Terminal Elimination Half-life (t1/2) of ZTI-01

  Mean and standard deviation (SD) of the t1/2 (h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

  Day 2

• Terminal-phase Elimination Rate Constant (Lambdaz) of ZTI-01

  Mean and standard deviation (SD) of the lambdaz (/h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

  Day 2

• Time to Peak Concentration (Tmax) of ZTI-01

  Mean and standard deviation (SD) of the Tmax (h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 1 and Dose 3 using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

  Day 1 to Day 2

• Volume of Distribution at Steady State (Vss) of ZTI-01

  Mean and standard deviation (SD) of the Vss (L) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for plasma samples collected during the study. If the amount extrapolated portion of AUC 0-inf was \>20%, the estimated Vss value was excluded from statistical summaries of the parameter estimates.

  Day 2

Study Arms (5)

2-Hour Group

EXPERIMENTAL

ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 2 hours after start of third infusion dose. n = 6

Drug: Fosfomycin disodium

30-Minute Group

EXPERIMENTAL

ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 30 minutes after start of third infusion dose. n = 6

Drug: Fosfomycin disodium

5-Hour Group

EXPERIMENTAL

ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 5 hours after start of third infusion dose. n = 6

Drug: Fosfomycin disodium

75-Minute Group

EXPERIMENTAL

ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 75 minutes after start of third infusion dose. n = 6

Drug: Fosfomycin disodium

8-Hour Group

EXPERIMENTAL

ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 8 hours after start of third infusion dose. n = 6

Drug: Fosfomycin disodium

Interventions

Fosfomycin disodium DRUG

Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.

2-Hour Group; 30-Minute Group; 5-Hour Group; 75-Minute Group; 8-Hour Group

Eligibility Criteria

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

You may qualify if:

• Healthy\* men and women aged 18-45 years with no clinically significant findings\*\* at Screening and Baseline (Day -1 to Day 1)

You may not qualify if:

• \*\*Including findings on medical history, physical exam, vital signs, 12-lead Electrocardiogram (ECG), or clinical laboratory tests.
• Body Mass Index (BMI) = 18 - 30 kg / m\^2, inclusive, and body weight \> 50 kg (110 lbs).
• Females who have been surgically sterilized via bilateral oophorectomy and/or hysterectomy at least 90 days prior to Screening are considered lacking childbearing potential and will be eligible\*.
• \*Postmenopausal females are not eligible, as the definition of menopause would require age \> 45, and all subjects in this study are age \< / = 45.
• Females of childbearing potential must have a negative serum pregnancy test at Screening, a negative urine pregnancy test at Baseline (Day -1 to Day 1), and must use acceptable contraception\*.
• \*Acceptable contraception methods are restricted to surgical sterilization (bilateral tubal ligation) or successful Essure placement (permanent, non-surgical, non-hormonal sterilization with documented radiological confirmation at least 90 days after the procedure), use of long-acting reversible contraceptive devices (progestin-releasing subdermal implants \[Nexplanon and Implanon, Merck\], copper intrauterine devices \[Paragard, Teva\], and levonorgestrel-releasing intrauterine devices \[Mirena, Bayer; Skyla, Bayer; Liletta, Allergan/Medicines360\]), licensed hormonal products such as injectables or oral contraceptives, barrier methods such as condoms or diaphragms with spermicidal agents, and abstinence from sexual intercourse with a male partner. Subjects must have used the above-listed method for a minimum of 30 days prior to the first dose of study drug and be willing to use the method for at least 30 days after the final dose of study drug.
• Male subjects\* whose partners are of childbearing age or pregnant must be willing to use condoms during the study and through the Day 3 follow-up call.
• \*including men who have had vasectomies
• Able to abstain from alcoholic beverages within 48 hours before Baseline (Day -1 to Day 1) and throughout the Treatment Phase.
• Able to abstain from caffeine use within 7 days before Baseline (Day -1 to Day 1) and throughout the inpatient period.
• Willing to remain in Duke Early Phase Research Unit (DEPRU) during the Baseline and Treatment Phases.
• Have a high probability for compliance and completion of the trial.
• Sign a dated, witnessed, written Informed Consent Form (ICF).
• Have adequate venous access for infusions and blood draws.
• Any surgical or medical condition that in the opinion of the investigator could interfere with drug absorption, distribution, metabolism, or excretion.

Sponsors & Collaborators

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

Study Sites (1)

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, 27704, United States

Location

Related Publications (1)

• Boole L, Yang Z, Bergin SP, Tighe RM, Randolph E, Hauser B, Gu K, Ghazaryan V, Wall A, Weigand K, Walter EB, Que LG. Evaluation of the safety profile and intrapulmonary pharmacokinetics of intravenous fosfomycin in healthy adults. Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0139524. doi: 10.1128/aac.01395-24. Epub 2025 Jan 8.

  PMID: 39772650 DERIVED

MeSH Terms

Conditions

Bacterial Infections

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: Emmanuel Walter, MD, MPH
• Organization: Duke Vaccine and Trials Unit

chip.walter@duke.edu

919-620-5346

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: March 28, 2019
• First Posted: April 10, 2019
• Study Start: June 27, 2019
• Primary Completion: December 17, 2020
• Study Completion: December 17, 2020
• Last Updated: October 23, 2023
• Results First Posted: January 19, 2022

Record last verified: 2020-03-13

Locations

US (1)