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

• Published in: Antimicrobial agents and chemotherapy Vol. 62; no. 8
• Main Authors: Wenzler, Eric, Bleasdale, Susan C., Sikka, Monica, Bunnell, Kristen L., Finnemeyer, Matthew, Rosenkranz, Susan L., Danziger, Larry H., Rodvold, Keith A.
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.08.2018
• Subjects: Anti-Bacterial Agents; Fosfomycin; Pharmacology; pharmacokinetics; fosfomycin; safety; tolerability; antimicrobial safety
• DOI: 10.1128/AAC.00464-18
• ISSN: 0066-4804; 1098-6596

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. 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.)