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

NCT02570074 | Completed Phase 1 Results DMC

• 2 other identifiers: Pro000661021UM1AI104681-01
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Healthy Subjects

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (20)

• 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

Study Arms (2)

Fosfomycin - 3 doses QoD/7 doses QD

EXPERIMENTAL

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

Fosfomycin - 7 doses QD/3 doses QoD

EXPERIMENTAL

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

Interventions

Fosfomycin DRUG

Broad spectrum antibiotic

Fosfomycin - 3 doses QoD/7 doses QD; Fosfomycin - 7 doses QD/3 doses QoD

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vance Fowler, M.D.: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

Related Publications (2)

• Wenzler E, Meyer KM, Bleasdale SC, Sikka M, Mendes RE, Bunnell KL, Finnemeyer M, Rosenkranz SL, Danziger LH, Rodvold KA. Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects. Antimicrob Agents Chemother. 2020 Jan 27;64(2):e02102-19. doi: 10.1128/AAC.02102-19. Print 2020 Jan 27.

  PMID: 31767717 DERIVED

• Wenzler E, Bleasdale SC, Sikka M, Bunnell KL, Finnemeyer M, Rosenkranz SL, Danziger LH, Rodvold KA; Antibacterial Resistance Leadership Group. Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants. Antimicrob Agents Chemother. 2018 Jul 27;62(8):e00464-18. doi: 10.1128/AAC.00464-18. Print 2018 Aug.

  PMID: 29891606 DERIVED

MeSH Terms

Interventions

Fosfomycin

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Results Point of Contact

• Title: Keith A. Rodvold, PharmD, FCCP, FIDSA
• Organization: University of Illinois at Chicago

kar@uic.edu

312-996-3341

Study Officials

• Vance Fowler, MD

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 6, 2015
• First Posted: October 7, 2015
• Study Start: January 1, 2016
• Primary Completion: September 1, 2016
• Study Completion: November 1, 2016
• Last Updated: July 30, 2019
• Results First Posted: July 30, 2019

Record last verified: 2019-07

Locations

US (1)