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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Fosfomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Male and female participants between 18 to 55 years old. 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. Nonsmokers defined as abstinence from cigarette smoking for the previous 6 months before enrollment into the study. Provide a signed and dated written informed consent prior to any study-specific procedures (including screening procedures). Body weight ≥50 kg Body mass index (BMI) 18.5-29.9 kg/m2 Exclusion Criteria: 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. History of significant cardiac, neurological, thyroid, muscular, or immune disorder. 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 Estimated creatinine clearance (CLCR) <60 ml/minute as determined by Cockcroft-Gault equation Positive serum pregnancy test. Currently breast feeding. 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. 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. 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. 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. Those who, in the opinion of the site investigator, have a risk of non-compliance with study procedures. QTc interval with Fredericia correction >450ms or any other clinically relevant ECG abnormalities

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fosfomycin - 3 doses QoD/7 doses QD<br>Fosfomycin given as a 3 gm dose, every other day for 3 doses, followed by 3 gm dose, once a day for 7 doses. | Drug: Fosfomycin<br>* Broad spectrum antibiotic<br>|
| Experimental: Fosfomycin - 7 doses QD/3 doses QoD<br>Fosfomycin given as a 3 gm dose, once a day for 7 doses, followed by 3 gm dose, every other day for 3 doses. | Drug: Fosfomycin<br>* Broad spectrum antibiotic<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number (%) of Grade 2 or Higher AEs Regardless of Relationship to Study Drug |  | 3 months | 
| Day 1: Plasma PK Concentrations [mg/L] | Day 1 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose | Day 1: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose | 
| Day 5: Plasma PK Concentrations [mg/L] | Day 5 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose | Day 5: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose | 
| Maximum Plasma Concentration (Cmax) | To estimate the fosfomycin pharmacokinetic parameter maximum plasma concentration (Cmax) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants | 24 hours | 
| Day 1: Area Under the Concentration Time Curve (AUC 0-infinity) | To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-infinity) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants | 24 hours | 
| Day 5: Area Under the Concentration Time Curve (AUC Tau-infinity) | To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-tau) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants | 24 hours | 
| Number of Subjects Who Prematurely Discontinue Study Drug |  | Dosing period: 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Body Clearance (CL) |  | Pooled over 24 hours: Day 1 | 
| Apparent Volume of Distribution (Vss) |  | Pooled over 24 hours at Day 1 and Day 5 | 
| Elimination Rate Constant (z) |  | Pooled over 24 hours at Day 1 and Day 5 | 
| Elimination Half-life (t½) |  | Pooled over 24 hours at Day 1 and Day 5 | 
| Renal Clearance (CLR) |  | Pooled over 24 hours at Day 1 and Day 5 | 
| Amount Excreted in the Urine (Ae) |  | Pooled over 24 hours at Day 1 and Day 5 | 
| Urinary Bactericidal (UBT) Titers for E. Coli ATCC 25922 | UBT for E.coli ATCC 25922 | 3 months | 
| Urinary Bactericidal Kinetics (UBK) |  | 3 months | 
| Urine Fosfomycin Concentrations [mg/L] | Urine Fosfomycin concentrations [mg/L] | Day 1: 24 hours | 
| UBT-time Curve (AUBT24) | For pathogens E. coli ATCC 25922, E. coli ATCC BAA-2323, K. pneumoniae ATCC 33495, K. pneumoniae ATCC 700603 and P. mirabilis ATCC 35659 | 24 hours at Day 1 and Day 5 | 
| Urine Fosfomycin Concentrations [mg/L] | Urine Fosfomycin concentrations [mg/L] | Day 5: 24 hours | 
| Urinary Bactericidal (UBT) Titers for E. Coli ATCC BAA-2323 | UBT for E. Coli ATCC BAA-2323 | 24 hours on Day 1 and Day 5 | 
| Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 33495 | UBT for E.coli K. Pneumoniae ATCC 33495 | 24 hours on Day 1 and Day 5 | 
| Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 700603 | UBT for K. Pneumoniae ATCC 700603 | 24 hours on Day 1 and Day 5 | 
| Urinary Bactericidal (UBT) Titers for P. Mirabilis ATCC 35659 | UBT for P. Mirabilis ATCC 35659 | 24 hours on Day 1 and Day 5 | 
| Urinary Inhibitory (UIT) Titers for E. Coli ATCC 25922 | UIT for E.coli ATCC 25922 | 24 hours on Day 1 and Day 5 | 
| Urinary Inhibitory (UIT) Titers for E. Coli ATCC BAA-2323 | UIT for E. Coli ATCC BAA-2323 | 24 hours on Day 1 and Day 5 | 
| Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 33495 | UIT for E.coli K. Pneumoniae ATCC 33495 | 24 hours on Day 1 and Day 5 | 
| Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 700603 | UIT for K. Pneumoniae ATCC 700603 | 24 hours on Day 1 and Day 5 | 
| Urinary Inhibitory (UIT) Titers for P. Mirabilis ATCC 35659 | UIT for P. Mirabilis ATCC 35659 | 24 hours on Day 1 and Day 5 |