Intravenous Fosfomycin Pharmacokinetics Study
Condition: Bacterial Infection; Multiple-drug Resistance; Pathogen Resistance
MeSH terms: Bacterial Infections
Intervention: Fosfomycin disodium
Intervention description: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.
Intervention MeSH terms: Fosfomycin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Adults; Fosfomycin Disodium; Healthy; Intrapulmonary; Intravenous; Pharmacokinetics; Phase 1; ZTI-01

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.
    

Eligibility criteria:

        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.

        Exclusion Criteria:

          1. Any surgical or medical condition that in the opinion of the investigator could
             interfere with drug absorption, distribution, metabolism, or excretion.

          2. Any surgical or medical condition that in the opinion of the investigator may place
             the subject at increased risk while participating in the trial.

          3. History or presence of cardiovascular disease including coronary artery disease and
             chronic hypertension (systolic pressure > 140 mmHg or diastolic pressure > 90 mmHg).

          4. Abnormal Electrocardiogram (ECG) at screening, as determined by the investigator to be
             clinically significant.

          5. History or presence of renal impairment or chronic renal disease.

          6. History or presence of liver disease (Alanine Aminotransferase (ALT), Aspartate
             Aminotransferase (AST), or total bilirubin above the upper limit of normal).

          7. History or presence of chronic pulmonary disease, including asthma, requiring use of
             medication in the year before screening.

          8. History of intolerance or hypersensitivity to phosphonic acid derivative antibiotics
             or any of its constituents (i.e., oral or intravenous fosfomycin).

          9. Have cancer or have a history of cancer within the past 5 years, with the exception of
             non-melanomatous skin cancer, treated, without evidence of recurrence.

         10. Any medical condition that prevents a subject from undergoing bronchoscopy with
             bronchoalveolar lavage (BAL).

         11. Serum creatinine above the upper limit of normal, or estimated creatinine clearance
             (CrCl) < 60 mL / min as determined by Cockcroft-Gault equation*.

             *Cockcroft-Gault equation where age is in years, weight is in kilograms, and serum Cr
             is in mg/dL units: Males: CrCl (mL / min) = (140 - age) x Weight / (72 x Cr) Females:
             CrCl (mL / min) = [(140 - age) x Weight / (72 x Cr)] x 0.85

         12. History of regular alcohol consumption within 6 months of Baseline (Day -1 to Day 1)*.

             *History of regular alcohol consumption is defined as an average weekly intake of > 14
             drinks for males or > 7 drinks for females. One drink is equivalent to 12 g of
             alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine, or 1.5 ounces (45 mL)
             of 80 proof distilled spirits.

         13. History of > / = 10 pack-years smoking, or history of any nicotine use* in the 6
             months before Baseline (Day -1 to Day 1)** or positive urinine cotinine screen at
             Basline (Day -1 to Day 1).

             *Including cigarettes, pipe, cigar, chewing tobacco, nicotine patch.

             **A positive urine cotinine at screening is allowed if negative at baseline.

         14. History of illicit drug use within 6 months of Baseline (Day -1 to Day 1)*.

             *Use of cannabinoids within 1 month of Baseline (Day -1 to Day 1) is excluded, but
             other use of cannabinoids within 6 months is permitted.

         15. Use of any prescription drugs, except acceptable contraception methods listed above,
             within 30 days of Baseline (Day -1 to Day 1).

         16. Involvement in other investigational studies of any type (drugs, devices, procedures)
             within 30 days of Baseline (Day -1 to Day 1).

         17. Blood or blood products donation within 30 days of Baseline (Day -1 to Day 1).

         18. Planning egg or sperm donation any time before Day 3 follow-up call.

         19. Use of any non-prescription medications, vitamins, consumption > 2 times/week of
             products containing genuine licorice, caffeine, or dietary or herbal supplements
             within 7 days of Baseline (Day -1 to Day 1)*.

             *Excluded from this list is intermittent use of acetaminophen at doses < / = 2 g /
             day. Herbal supplements must be discontinued 7 days before the initial dose of study
             drug on Day 1.

         20. Presence of any acute illness, including febrile illness with temperature > 37.8
             degrees Celsius (> 100.0 degrees Fahrenheit), within 7 days of Baseline (Day -1 to Day
             1).

         21. Currently pregnant or breastfeeding as determined by subject report.

         22. Positive tests for human immunodeficiency virus (HIV) 1 and 2 antibodies, hepatitis B
             surface antigen (HBsAg), or hepatitis C virus (HCV) antibody.

         23. Positive urine drug or positive breathalyzer test for alcohol at Screening or Baseline
             (Day -1 to Day 1) or positive cotinine at Baseline (Day -1 to Day 1).

         24. Weight loss or gain of > 10% within 30 days of Baseline (Day -1 to Day 1).

         25. Any laboratory value at screening or enrollment that is Grade 2 or more. A laboratory
             value that is Grade 1 will be allowed if not considered to be clinically significant
             by the investigator*.

             *Excluded from this list of permissible Grade 1 laboratory values are (ALT), (AST), or
             Total bilirubin per Exclusion Criteria 6 and serum creatinine per Exclusion Criteria
             #11; and serum electrolytes including sodium, potassium, calcium, phosphorus and
             magnesium.

         26. History of infection with SARS-CoV-2 (COVID-19) within 3 months of Baseline (Day -1 to
             Day 1) or unresolved symptoms of COVID-19.

         27. Positive test for SARS-CoV-2 (COVID-19) at Screening or Baseline (Day -1 to Day 1)
             within 72 hours of admission