Phase I Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants (PROOF) [PublishAheadOfPrint]

The pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period crossover study. Serial blood (n=11) and urine samples (n=4 collection intervals) were collected before and up to 24 hours after dosing on Days 1 and 5 along with pre-dose concentrations on Days 3 and 7. PK parameters were similar between Days 1 and 5 within and between dosing regimens. The mean (±SD) PK parameters of fosfomycin in plasma on Day 5 during the QOD and QD dosing regimens, respectively, were: C_max= 24.4±6.2 vs 23.8±5.6 μg/mL, T_max= 2.2±0.7 vs. 2.0±0.4 h, V_d/F= 141±67.9 vs. 147±67.6 liters, CL/F= 21.4±8.0 vs. 20.4±5.3 liters/h, CL_R= 7.5±4.1 vs. 7.3±3.5 liters/h, AUC_0-24= 151.6±35.6 vs. 156.6±42.5 μg⋅h/mL, and t_1/2= 4.5±1.1 vs. 5.0±1.7 h. Urine concentrations peaked at approximately 600 μg/mL through the 0-8 hours urine collection intervals but displayed significant interindividual variability. Roughly 35-40% of the 3 g dose was excreted in the urine by 24 hours post-dose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower in the QD regimen compared to the QOD regimen (61% vs. 77%, P<0.0001). Further studies establishing the clinical benefit:risk ratio of repeated dosing regimens of oral fosfomycin tromethamine are warranted.

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