Phase I Study to Evaluate the Pharmacokinetics of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

Abstract

Background

There is a lack of robust pharmacokinetic (PK) data to support the clinical use of oral fosfomycin tromethamine (FOS) and no published trials have evaluated the PK of FOS after repeated doses. The objective of this study was to detail the PK of FOS after every other day (QOD) and daily (QD) dosing.

Methods

Phase I, randomized, two-period crossover trial (NCT02570074 PROOF, Award number UM1AI104681- Antibacterial Resistance Leadership Group) conducted in healthy adult subjects. Subjects received 3 g FOS either QOD for 3 doses then QD for 7 doses, or vice versa, separated by a washout period. 10 blood samples were collected serially before and through 24 hours post-dose after a single dose on day 1 and after multiple doses on day 5. Trough concentrations were also collected on days 3 and 7. Plasma concentrations were analyzed via LC/MS-MS. Noncompartmental PK analyses were performed via WinNonlin.

Results

18 PK evaluable subjects were 50% male, 72% White, mean (±SD) age 28 ± 7 years, weight 75.4 ± 11.5 kg, and estimated CrCl 110 ± 19.9 mL/minute. Mean (±SD) plasma PK parameters are shown in Table 1. Mean (±SD) trough plasma concentrations (mg/L) on days 3 and 7 in the QOD regimen were 0.2 ± 0.3 and 0.1 ± 0.2 and in the QD regimen were 1.3 ± 1.1 and 1.3 ± 1.1.

Conclusion

This study provides important information on the time course and magnitude of plasma concentrations of FOS after previously unstudied dosing regimens. Observed PK profiles were similar between QOD and QD dosing on days 1 and 5. Maximum plasma concentrations were below the CLSI breakpoint for susceptibility to E. coli of 64 mg/L for all subjects. Mean trough concentrations were higher after QD dosing, but were below 2 mg/L. Regardless of the PK/pharmacodynamic driver, FOS dosed either QOD or QD may not be adequate to treat extra-urogenital infections with elevated MICs given the low systemic exposures after oral dosing.RegimenQODQDPK parameterDay 1Day 5Day 1Day 5C_max (mg/L)23.8 ± 7.524.4 ± 6.223.5 ± 6.623.8 ± 5.6T_max (hours)2.0 ± 0.52.2 ± 0.72.1 ± 0.62.0 ± 0.4V_d/F (L)172 ± 70.5140.6 ± 67.9138.6 ± 57.4146.7 ± 67.6CL_T/F (L/hours)21.6 ± 6.821.4 ± 8.022.2 ± 5.920.4 ± 5.3CL_R (L/hours)7.1 ± 3.67.5 ± 4.18.1 ± 5.67.3 ± 3.5AUC (mg·hours/L)148.8 ± 35.4^a151.6 ± 35.6^b149.8 ± 67.3^a156.6 ± 42.5^bt_1/2 (hours)5.6 ± 1.54.5 ± 1.14.4 ± 1.35.0 ± 1.7^aAUC_0-∞,^bAUC_0-24

Disclosures

All authors: No reported disclosures.

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