Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Abstract

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 and 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 (n = 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (C_max) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time to C_max (T_max) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CL_R) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC_0-24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t_1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%; P < 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.).

Keywords: antimicrobial safety; fosfomycin; pharmacokinetics; safety; tolerability.

FIG 1

Mean (± SD) concentration-versus-time profiles of fosfomycin in plasma after oral administration of 3 g oral fosfomycin tromethamine on study day 1 (A) and study day 5 (B). The QOD dosing regimen data are illustrated by open triangles and a dashed line, and the QD regimen data are illustrated by filled circles and a solid line. The y axis is on a log scale.

FIG 2

Mean (± SD) concentration-versus-time profiles of fosfomycin in urine after oral administration of 3 g oral fosfomycin tromethamine on study day 1 (A) and study day 5 (B). The QOD dosing regimen data are illustrated by open triangles and a dashed line, and the QD regimen data are illustrated by filled circles and a solid line.

FIG 3

Mean (± SD) cumulative fractions (percentages) of the fosfomycin dose excreted in urine over time following oral administration of 3 g oral fosfomycin tromethamine on study day 1 (A) and study day 5 (B). The QOD dosing regimen data are illustrated by open triangles and a dashed line, and the QD regimen data are illustrated by filled circles and a solid line.

FIG 4

Days of diarrhea per subject and study day during the QOD regimen (A) and the QD regimen (B). Cases of CTCAE grade 1 diarrhea are shaded in black, and cases of grade 2 diarrhea are shown in red. Gray shaded days indicate that no diarrhea events occurred during these at-risk days. Unshaded days represent days beyond a participant's follow-up period. Asterisks represent days of study drug administration.