Phase I Study To Evaluate The Safety And Tolerability Of Two Dosing Regimens Of Oral Fosfomycin Tromethamine In Healthy Adult Participants

Abstract Background The safety and tolerability of oral fosfomycin tromethamine (FOS) after multiple doses has not been well characterized in a controlled trial. A primary objective of this phase 1 trial was to evaluate the safety and tolerability of two dosing regimens of FOS in healthy adult subjects (NCT02570074 PROOF, Award UM1AI104681 Antibacterial Resistance Leadership Group). Methods Subjects received 3 g FOS orally either QOD for 3 doses then QD for 7 doses, or vice versa, separated by a washout period. 19 subjects received at least 1 dose and were included in the safety population. Safety was monitored via laboratory tests, physical examinations, 12-lead ECGs, vital signs, and monitoring of adverse events (AE) from the first dose of study drug to 60 days after the last dose. Severity of AEs was assessed according to the Common Terminology Criteria for Adverse Events and MedDRA coded. Results Subjects were 53% male, 68% White, mean (±SD) age 28 ± 7 years, mean (±SD) weight 75.7 ± 11.3 kg, mean (±SD) estimated CrCl 109.6 ± 19.4 mL/minute. No subject discontinued FOS due to an AE and there were no Grade 4 or life-threatening AEs. One Grade 3 AST elevation occurred in 1 subject on the day of the last QOD dose and one Grade 3 AE of C. difficile colitis occurred in 1 subject 14 days after the last QD dose. Both events resolved without sequelae. The most commonly reported AE overall was Grade 1 diarrhea (defined as an increase of up to 3 stools/day above baseline) which represented 57% (52/91) of all AEs. More than 75% of subjects reported some type of gastrointesintal AE during each regimen (Table 1). Conclusion The incidence of AEs in this study of healthy subjects receiving multiple oral doses of FOS was high. The majority of AEs were gastrointestinal and nearly every young, healthy subject experienced an AE. The clinical use of repeated dosing regimens of FOS is likely to be associated with a higher incidence of gastrointestinal AEs and poorer tolerability. Disclosures All authors: No reported disclosures. Table 1. Summary of AEs with ≥5% incidence QOD (N = 19) QD (N = 18) AE 17 (89) 16 (89) Gastrointestinal 15 (79) 16 (89) Skin and soft tissue 3 (16) 2 (11) Nervous system 1 (5) 3 (17) Renal 1 (5) - Infections - 2 (11) Psychiatric - 1 (6) Hepatic 1 (5) - Ear - 1 (6) Respiratory 1 (5) - General disorders - 1 (6) *Presented as number of subjects (%)