PK/PD and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adults
Condition: Healthy Subjects
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      The study was designed as a randomized, two-way crossover trial involving up to 24 randomized
      participants with an anticipated drop-out rate no higher than 25% to give a total of 18
      evaluable healthy adult participants. The study was fully explained to each participant,
      informed consent was obtained, and an IRB-approved informed consent form was signed before
      any study procedures were initiated. All participants underwent screening assessments within
      30 days prior to the initial dosing to determine their eligibility for enrollment into the
      study. All participants met the inclusion and exclusion criteria and underwent screening
      procedures that included a complete medical history, physical examination, assessment of
      clinical laboratory parameters (chemistry and hematology), ECG, and pregnancy test (females
      of child bearing potential only).

      Randomization was stratified by gender, using permuted blocks. Within each gender, eligible
      participants were randomized with equal probability to one of the 2 treatment sequences shown
      in Table 3. According to the sequence to which the participant was randomized, the
      participant initially received one of two oral dosage regimens of fosfomycin: 3 g every other
      day x 3 doses or 3 g once-daily x 7 doses. After completion of the initial dosing regimen
      each participant was crossed over to receive the other dosing regimen. There was a minimum
      5-day, and a recommended maximum 14-day, washout period prior to starting the next dosing
      regimen. Blood and urine samples were collected throughout the study as well as detailed drug
      administration and adverse event data for each participant.

      Fosfomycin tromethamine sachet (Monurol™) was used in this study. Each participant was
      instructed how to stir and dissolve the single-dose sachet into 3 to 4 ounces of water, and
      take each dose immediately after dissolving in water. Compliance was assessed by participant
      interviews (every 2 days) and counting of empty of sachets.

      Participants reported to the outpatient study center on Day -30 to -1 for study criteria
      review, clinical assessment, and blood collection for screening laboratory tests prior to
      fosfomycin administration. Each participant participated in the study up to 120 days (i.e.,
      screening visit; day -1 for clinical assessment and blood collection; days 1-7 for fosfomycin
      administration and sample collection period; and day 8-10 for follow-up assessment; crossed
      over to receive the other dosing regimen and schedule of events.
    

Intervention name(s): Fosfomycin
Intervention type(s): Drug
Intervention description(s): Broad spectrum antibiotic
Intervention MeSH terms: Fosfomycin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science