PK/PD and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adults — PROOF  

Healthy Subjects Clinical Trial

Official title: Phase I Study to Evaluate Pharmacokinetics, Pharmacodynamics and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Healthy Subjects

• NCT number: NCT02570074
• Study type: Interventional
• Source: Duke University
• Status: Completed
• Phase: Phase 1
• Start date: January 2016
• Completion date: November 2016