Fosfomycin clinical pharmacology

# CLINICAL PHARMACOLOGY
==Absorption:==Fosfomycin tromethamine is rapidly absorbed following oral administration and converted to the free acid, fosfomycin. Absolute oral bioavailability under fasting conditions is 37%. After a single 3-gm dose of MONUROL, the mean ( 1 SD) maximum serum concentration (Cmax) achieved was 26.1 ( 9.1) g/mL within 2 hours. The oral bioavailability of fosfomycin is reduced to 30% under fed conditions. Following a single 3-gm oral dose of MONUROL with a high-fat meal, the mean Cmaxachieved was 17.6 ( 4.4) g/mL within 4 hours.
Cimetidine does not affect the pharmacokinetics of fosfomycin when coadministered with MONUROL. Metoclopramide lowers the serum concentrations and urinary excretion of fosfomycin when coadministered with MONUROL. (SeePRECAUTIONS, Drug Interactions)
==Distribution:==The mean apparent steady-state volume of distribution (Vss) is 136.1 (44.1) L following oral administration of MONUROL. Fosfomycin is not bound to plasma proteins.
Fosfomycin is distributed to the kidneys, bladder wall, prostate, and seminal vesicles. Following a 50 mg/Kg dose of fosfomycin to patients undergoing urological surgery for bladder carcinoma, the mean concentration of fosfomycin in the bladder, taken at a distance from the neoplastic site, was 18.0 g per gram of tissue at 3 hours after dosing. Fosfomycin has been shown to cross the placental barrier in animals and man.
===Excretion:====Fosfomycin is excreted unchanged in both urine and feces. Following oral administration of MONUROL, the mean total body clearance (CLTB) and mean renal clearance (CLR) of fosfomycin were 16.9 ( 3.5) L/hr and 6.3 ( 1.7) L/hr, respectively. Approximately 38% of a 3-gm dose of MONUROL is recovered from urine, and 18% is recovered from feces. Following intravenous administration, the mean CLTBand mean CLRof fosfomycin were 6.1 ( 1.0) L/hr and 5.5 (1.2) L/hr, respectively.
A mean urine fosfomycin concentration of 706 ( 466) g/mL was attained within 2-4 hours after a single oral 3-gm dose of MONUROL under fasting conditions. The mean urinary concentration of fosfomycin was 10 g/mL in samples collected 72-84 hours following a single oral dose of MONUROL.
Following a 3-gm dose of MONUROL administered with a high fat meal, a mean urine fosfomycin concentration of 537 ( 252) g/mL was attained within 6-8 hours. Although the rate of urinary excretion of fosfomycin was reduced under fed conditions, the cumulative amount of fosfomycin excreted in the urine was the same, 1118 ( 201) mg (fed) vs. 1140 mg ( 238) (fasting). Further, urinary concentrations equal to or greaterthan 100 g/mL were maintained for the same duration, 26 hours, indicating that MONUROL can be taken without regard to food.
Following oral administration of MONUROL, the mean half-life for elimination (t1/2) is 5.7 ( 2.8) hours.

## Special Populations:
Geriatric:Based on limited data regarding 24-hour urinary drug concentrations, no differences in urinary excretion of fosfomycin have been observed in elderly subjects. No dosage adjustment is necessary in the elderly.
Gender:There are no gender differences in the pharmacokinetics of fosfomycin.
Renal Insufficiency:In 5 anuric patients undergoing hemodialysis, the t1/2of fosfomycin during hemodialysis was 40 hours. In patients with varying degrees of renal impairment (creatinine clearances varying from 54 mL/min to 7 mL/min), the t1/2of fosfomycin increased from 11 hours to 50 hours. The percent of fosfomycin recovered in urine decreased from 32% to 11% indicating that renal impairment significantly decreases the excretion of fosfomycin.