Phase I study to evaluate the pharmacokinetics, safety, and tolerability of two dosing regimens of oral fosfomycin tromethamine in healthy adult participants

Antibacterial Resistance Leadership Group

Research output: Contribution to journalArticle

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 (Cmax) 24.4 6.2 versus 23.8 5.6 g/ml, time to Cmax (Tmax) 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 (CLR) 7.5 4.1 versus 7.3 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) 151.6 35.6 versus 156.6 42.5 g · h/ml, and elimination half-life (t1/2) 4.5 1.1 versus 5.0 1.7 h. Urine concentrations peaked at approximately 600 g/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.)

Original languageEnglish (US)
Article numbere00464-18
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number8
DOIs
StatePublished - Aug 1 2018

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Fosfomycin
Healthy Volunteers
Pharmacokinetics
Urine
Safety
Urine Specimen Collection
Cross-Over Studies
Half-Life
Diarrhea
Odds Ratio
Kidney
Serum
Pharmaceutical Preparations

Keywords

  • Antimicrobial safety
  • Fosfomycin
  • Pharmacokinetics
  • Safety
  • Tolerability

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Phase I study to evaluate the pharmacokinetics, safety, and tolerability of two dosing regimens of oral fosfomycin tromethamine in healthy adult participants. / Antibacterial Resistance Leadership Group.

In: Antimicrobial Agents and Chemotherapy, Vol. 62, No. 8, e00464-18, 01.08.2018.

Research output: Contribution to journalArticle

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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 (Cmax) 24.4 6.2 versus 23.8 5.6 g/ml, time to Cmax (Tmax) 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 (CLR) 7.5 4.1 versus 7.3 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) 151.6 35.6 versus 156.6 42.5 g · h/ml, and elimination half-life (t1/2) 4.5 1.1 versus 5.0 1.7 h. Urine concentrations peaked at approximately 600 g/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.)",
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AU - Antibacterial Resistance Leadership Group

AU - Wenzler, Eric

AU - Bleasdale, Susan C.

AU - Sikka, Monica

AU - Bunnell, Kristen L.

AU - Finnemeyer, Matthew

AU - Rosenkranz, Susan L.

AU - Danziger, Larry H.

AU - Rodvold, Keith A.

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N2 - 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 (Cmax) 24.4 6.2 versus 23.8 5.6 g/ml, time to Cmax (Tmax) 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 (CLR) 7.5 4.1 versus 7.3 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) 151.6 35.6 versus 156.6 42.5 g · h/ml, and elimination half-life (t1/2) 4.5 1.1 versus 5.0 1.7 h. Urine concentrations peaked at approximately 600 g/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.)

AB - 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 (Cmax) 24.4 6.2 versus 23.8 5.6 g/ml, time to Cmax (Tmax) 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 (CLR) 7.5 4.1 versus 7.3 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) 151.6 35.6 versus 156.6 42.5 g · h/ml, and elimination half-life (t1/2) 4.5 1.1 versus 5.0 1.7 h. Urine concentrations peaked at approximately 600 g/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.)

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KW - Pharmacokinetics

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KW - Tolerability

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