PK/PD and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adults
Condition: Healthy Subjects
Intervention: Fosfomycin
Intervention description: Broad spectrum antibiotic
Intervention MeSH terms: Fosfomycin
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      Oral dosage regimens for fosfomycin tromethamine (Monurol™) are not established for the
      treatment of cUTI. The most common and recommended adult dosage regimen in the literature is
      a single-dose sachet containing the equivalent of 3 grams of fosfomycin administered every
      other day (QOD) for a total of three doses.

      There are a myriad of different oral fosfomycin dosing regimens currently being used in
      clinical practice, including up to 3 grams orally twice daily for 7-21 days, but these
      regimens are not based on solid pharmacokinetic, pharmacodynamic or safety rationale. Initial
      pharmacokinetic studies performed with oral fosfomycin tromethamine primarily examined single
      dose regimens and did not use modern day bioanalytical or pharmacokinetic techniques. As the
      use of fosfomycin becomes more pervasive in concordance with the increase in multidrug
      resistant pathogens, further pharmacokinetic and safety data are needed for more intensive
      dosing regimens to support its continued use.

      The rationale of this study is that oral fosfomycin tromethamine requires a modern
      pharmacokinetic-pharmacodynamic study to identify alternative oral dosage regimens that are
      appropriate and safe. This study provided safety/tolerability and clinical pharmacology
      information regarding two oral dosing regimens that may have application to treat various
      types of infections involving resistant pathogens or when other oral antibacterial options
      are not available.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The participant is healthy as judged by the site investigator with no clinically
             significant abnormality identified on a medical evaluation including history, physical
             examination, laboratory tests, blood pressure, and heart rate.

          2. Male and female participants between 18 to 55 years old.

          3. Female participants of childbearing potential (not surgically sterilized and between
             menarche and one-year post-menopause) must have a negative pregnancy test at the time
             of enrollment and must agree to use appropriate contraception for as long as they are
             taking the study drug and for 1 month afterwards. During the screening visit,
             participants will be instructed to use a second reliable method of birth control in
             accordance with the protocol during the study and for one month following. Medically
             acceptable contraceptives include:

               -  Surgical sterilization (such as a tubal ligation or hysterectomy)

               -  Approved hormonal contraceptives (such as birth control pills, patches, implants
                  or injections)

               -  Barrier methods (such as a condom or diaphragm) used with a spermicide, or

               -  An intrauterine device (IUD). i. NOTE: Contraceptive measures such as Plan B™,
                  sold for emergency use after unprotected sex, are not acceptable methods for
                  routine use.

          4. Nonsmokers defined as abstinence from cigarette smoking for the previous 6 months
             before enrollment into the study.

          5. Provide a signed and dated written informed consent prior to any study-specific
             procedures (including screening procedures).

          6. Body weight ≥50 kg

          7. Body mass index (BMI) 18.5-29.9 kg/m2

        Exclusion Criteria:

          1. History of significant hypersensitivity reaction or intolerance to fosfomycin
             tromethamine that in the opinion of the site investigator, contraindicates
             participation in the study. In addition, if heparin is used during pharmacokinetic
             sampling, participants with a history of sensitivity to heparin or heparin-induced
             thrombocytopenia should not be enrolled.

          2. History of significant cardiac, neurological, thyroid, muscular, or immune disorder.

          3. Any laboratory abnormality grade 2 or higher as defined according to the U.S.
             Department of Health and Human Services common terminology criteria for AEs (CTCAE).26

          4. Estimated creatinine clearance (CLCR) <60 ml/minute as determined by Cockcroft-Gault
             equation

          5. Positive serum pregnancy test.

          6. Currently breast feeding.

          7. History of alcohol or substance abuse or dependence within 6 months of the screening:
             History of regular alcohol consumption averaging >7 drinks/week for women or >14
             drinks/week for men. 1 drink is equivalent to 12g alcohol = 5 oz (150 mL) of wine or
             12 oz (360 mL) of beer or 1.5 oz (45 mL) of 80 proof distilled spirits.

          8. The use of prescription (except birth control pills or hormone replacement in females)
             or non-prescription drugs, including herbal and dietary supplements (including St.
             John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5
             half-lives (whichever is longer) prior to the first dose of study medication, unless
             in the opinion of site investigator the medication will not interfere with the study
             procedures or compromise participant safety.

          9. The participant has participated in a clinical trial and has received a drug or a new
             chemical entity within 30 days prior to the first dose of study medication.

         10. Participants who have donated blood to the extent where participation in the study
             would result in excess of 500 mL blood donated within a 56 day period.

         11. Those who, in the opinion of the site investigator, have a risk of non-compliance with
             study procedures.

         12. QTc interval with Fredericia correction >450ms or any other clinically relevant ECG
             abnormalities