Bacterial Infection, Multiple-drug Resistance, Pathogen Resistance
Conditions
Keywords
Adults, Fosfomycin Disodium, Healthy, Intrapulmonary, Intravenous, Pharmacokinetics, Phase 1, ZTI-01
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.
Detailed description
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.
Interventions
Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy\* men and women aged 18-45 years with no clinically significant findings\*\* at Screening and Baseline (Day -1 to Day 1) \*Healthy is defined by the absence of any medical condition described in the
Exclusion criteria
in a subject with a normal physical exam including vital signs. If the subject has another current, ongoing medical condition, the condition cannot meet any of the following criteria: 1) first diagnosed within 3 months of enrollment; 2) is worsening in terms of clinical outcome in the last 6 months; or 3) involves need for medication. \*\*Including findings on medical history, physical exam, vital signs, 12-lead Electrocardiogram (ECG), or clinical laboratory tests. 2. Body Mass Index (BMI) = 18 - 30 kg / m\^2, inclusive, and body weight \> 50 kg (110 lbs). 3. 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. 4. 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. 5. 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 6. Able to abstain from alcoholic beverages within 48 hours before Baseline (Day -1 to Day 1) and throughout the Treatment Phase. 7. Able to abstain from caffeine use within 7 days before Baseline (Day -1 to Day 1) and throughout the inpatient period. 8. Willing to remain in Duke Early Phase Research Unit (DEPRU) during the Baseline and Treatment Phases. 9. Have a high probability for compliance and completion of the trial. 10. Sign a dated, witnessed, written Informed Consent Form (ICF). 11. Have adequate venous access for infusions and blood draws.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 | Day 1 to Day 2 | 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). |
| Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments | Day 1 to Day 2 | 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. |
| Clearance (CL) of ZTI-01 | Day 2 | 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. |
| Intrapulmonary Pharmacokinetics of ZTI-01 | Day 2 | 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. |
| Maximum Measured Plasma Concentration (Cmax) of ZTI-01 | Day 1 to Day 2 | 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. |
| Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Day 1 to Day 2 | 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. |
| Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Day 1 to Day 2 | 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. |
| Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments | Day 1 to Day 2 | 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. |
| Number of Participants Experiencing Abnormal Physical Examination Findings | Day 1 to Day 2 | 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). |
| Number of Participants Experiencing Abnormal Vital Sign Measurements | Day 1 to Day 2 | 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. |
| Number of Participants Experiencing Adverse Events (AEs) | Day 1 to Day 3 | 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. |
| Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings | Day 1 to Day 2 | 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. |
| Terminal Elimination Half-life (t1/2) of ZTI-01 | Day 2 | 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. |
| Terminal-phase Elimination Rate Constant (Lambdaz) of ZTI-01 | Day 2 | 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. |
| Time to Peak Concentration (Tmax) of ZTI-01 | Day 1 to Day 2 | 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. |
| Volume of Distribution at Steady State (Vss) of ZTI-01 | Day 2 | 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. |
Countries
United States
Participant flow
Recruitment details
The study population included healthy male and female adults, aged 18-45 years, inclusive, with body mass index (BMI) 18-30 kg/m2, inclusive, and body weight \>50 kg (110 lbs) who met all eligibility criteria. Participants were enrolled between 27JUN2019 and 08DEC2020, and were recruited from the community at large.
Participants by arm
| Arm | Count |
|---|---|
| 30 Minute BAL 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.
BAL performed 30 minutes after start of third infusion dose. | 7 |
| 75 Minute BAL 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.
BAL performed 75 minutes after start of third infusion dose. | 6 |
| 2 Hour BAL 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.
BAL performed 2 hours after start of third infusion dose. | 7 |
| 5 Hour BAL 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.
BAL performed 5 hours after start of third infusion dose. | 13 |
| 8 Hour BAL 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.
BAL performed 8 hours after start of third infusion dose. | 6 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | 30 Minute BAL | Total | 8 Hour BAL | 5 Hour BAL | 2 Hour BAL | 75 Minute BAL |
|---|---|---|---|---|---|---|
| Age, Continuous | 31.3 years STANDARD_DEVIATION 6.5 | 31.4 years STANDARD_DEVIATION 6.5 | 30.3 years STANDARD_DEVIATION 9.4 | 32.3 years STANDARD_DEVIATION 6.6 | 31.4 years STANDARD_DEVIATION 6.8 | 31.2 years STANDARD_DEVIATION 4.6 |
| BMI | 24.31 kg/m^2 STANDARD_DEVIATION 3.35 | 25.54 kg/m^2 STANDARD_DEVIATION 2.84 | 25.27 kg/m^2 STANDARD_DEVIATION 2.4 | 26.89 kg/m^2 STANDARD_DEVIATION 2.99 | 25.47 kg/m^2 STANDARD_DEVIATION 2.68 | 24.6 kg/m^2 STANDARD_DEVIATION 2.11 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 34 Participants | 6 Participants | 10 Participants | 6 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Height | 170.26 cm STANDARD_DEVIATION 10.52 | 169.2 cm STANDARD_DEVIATION 8.62 | 173.28 cm STANDARD_DEVIATION 8.17 | 168.22 cm STANDARD_DEVIATION 8.44 | 163.07 cm STANDARD_DEVIATION 4.54 | 173 cm STANDARD_DEVIATION 8.67 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 15 Participants | 2 Participants | 5 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 16 Participants | 4 Participants | 5 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Female | 3 Participants | 18 Participants | 3 Participants | 7 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 4 Participants | 21 Participants | 3 Participants | 6 Participants | 3 Participants | 5 Participants |
| Weight | 70.64 kg STANDARD_DEVIATION 11.87 | 72.84 kg STANDARD_DEVIATION 10.59 | 75.78 kg STANDARD_DEVIATION 7.49 | 74.96 kg STANDARD_DEVIATION 12.68 | 67.6 kg STANDARD_DEVIATION 6.14 | 73.98 kg STANDARD_DEVIATION 11.26 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 39 |
| other Total, other adverse events | 38 / 39 |
| serious Total, serious adverse events | 0 / 39 |
Outcome results
Primary
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).
Time frame: Day 1 to Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZTI-01 All Participants | Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 | AUC 0-8, after Dose 1 | 780.9 h*ug/mL | Standard Deviation 112.2 |
| ZTI-01 All Participants | Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 | AUC 0-8, after Dose 3 | 959.4 h*ug/mL | Standard Deviation 147.5 |
| ZTI-01 All Participants | Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 | AUC 0-inf, after Dose 3 | 1086.0 h*ug/mL | Standard Deviation 183.3 |
Primary
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.
Time frame: Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZTI-01 All Participants | Clearance (CL) of ZTI-01 | 5.69 L/h | Standard Deviation 1.04 |
Primary
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.
Time frame: Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ZTI-01 All Participants | Intrapulmonary Pharmacokinetics of ZTI-01 | ELF | 31.8 Plasma percent penetration |
| ZTI-01 All Participants | Intrapulmonary Pharmacokinetics of ZTI-01 | AM | 17.5 Plasma percent penetration |
Primary
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.
Time frame: Day 1 to Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZTI-01 All Participants | Maximum Measured Plasma Concentration (Cmax) of ZTI-01 | Cmax, after Dose 1 | 297.5 ug/mL | Standard Deviation 46.074 |
| ZTI-01 All Participants | Maximum Measured Plasma Concentration (Cmax) of ZTI-01 | Cmax, after Dose 3 | 335.1 ug/mL | Standard Deviation 63.5872 |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Sodium - Increase | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Sodium - Decrease | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Potassium - Increase | 19 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Potassium - Decrease | 19 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Magnesium - Decrease | 31 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Calcium - Increase | 16 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Calcium - Decrease | 16 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Phosphorus - Decrease | 5 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Albumin - Decrease | 4 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Random Glucose - Increase | 8 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Random Glucose - Decrease | 8 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Blood Urea Nitrogen - Increase | 4 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Total Protein - Decrease | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Creatinine - Increase | 0 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Triglycerides - Increase | 5 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Total Cholesterol - Increase | 0 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Creatine Phosphokinase - Increase | 3 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Alkaline Phosphatase - Increase | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Aspartate Aminotransferase - Increase | 0 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Alanine Aminotransferase - Increase | 14 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Total Bilirubin - Increase | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Direct Bilirubin - Increase | 5 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments | Lactate Dehydrogenase - Increase | 0 Participants |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments | PT - Increase | 9 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments | aPTT - Increase | 6 Participants |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | WBC - Increase | 7 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Hemoglobin - Decrease | 7 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Platelets - Decrease | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | WBC - Decrease | 7 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Neutrophils - Decrease | 6 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Lymphocytes - Decrease | 0 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments | Eosinophils - Increase | 1 Participants |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments | Protein | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments | Glucose | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments | RBC Count | 1 Participants |
Primary
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).
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Physical Examination Findings | Abdomen | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Physical Examination Findings | Extremities | 3 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Physical Examination Findings | General Appearance | 4 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Physical Examination Findings | Musculoskeletal | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Physical Examination Findings | Skin | 2 Participants |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure - Decrease | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Systolic Blood Pressure - Increase | 3 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Diastolic Blood Pressure - Increase | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate - Decrease | 13 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Heart Rate - Increase | 6 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Respiratory Rate - Increase | 9 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Abnormal Vital Sign Measurements | Temperature - Increase | 0 Participants |
Primary
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.
Time frame: Day 1 to Day 3
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Cardiac disorders | 15 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Gastrointestinal disorders | 9 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | General disorders and administration site conditions | 10 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Investigations | 37 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Musculoskeletal and connective tissue disorders | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Nervous system disorders | 5 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Renal and urinary disorders | 1 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Respiratory, thoracic and mediastinal disorders | 14 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Skin and subcutaneous tissue disorders | 2 Participants |
| ZTI-01 All Participants | Number of Participants Experiencing Adverse Events (AEs) | Vascular disorders | 7 Participants |
Primary
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.
Time frame: Day 1 to Day 2
Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion).~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ZTI-01 All Participants | Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings | QTc Interval | 1 Participants |
| ZTI-01 All Participants | Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings | PR Interval | 0 Participants |
| ZTI-01 All Participants | Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings | QRS Duration | 0 Participants |
Primary
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.
Time frame: Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZTI-01 All Participants | Terminal Elimination Half-life (t1/2) of ZTI-01 | 2.62 h | Standard Deviation 0.36 |
Primary
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.
Time frame: Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZTI-01 All Participants | Terminal-phase Elimination Rate Constant (Lambdaz) of ZTI-01 | 0.2703 /h | Standard Deviation 0.0391 |
Primary
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.
Time frame: Day 1 to Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ZTI-01 All Participants | Time to Peak Concentration (Tmax) of ZTI-01 | Tmax, after Dose 1 | 1.07 h | Standard Deviation 0.06 |
| ZTI-01 All Participants | Time to Peak Concentration (Tmax) of ZTI-01 | Tmax, after Dose 3 | 1.06 h | Standard Deviation 0.05 |
Primary
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.
Time frame: Day 2
Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing.~All arms are reported jointly as all received the same dose, following the same dosing schedule.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ZTI-01 All Participants | Volume of Distribution at Steady State (Vss) of ZTI-01 | 18.08 L | Standard Deviation 2.8 |