Fosfomycin kinetics after intravenous and oral administration to human volunteers

Abstract

The pharmacokinetics of fosfomycin, administered intravenously and orally at two different doses (20 and 40 mg/kg of body weight), was studied in seven volunteers. The elimination profile of this antibiotic, when administered intravenously, followed a two-compartment kinetic model, independent of dosage, giving an elimination half-life of 2.23 ± 0.62 h and an average total volume of distribution at steady state of 0.34 liter/kg. Peak serum levels after rapid intravenous administration of 20 and 40 mg/kg were 132.1 ± 31.8 and 259.3 ± 32.5 ,ug/ml, respectively.Peak serum levels after oral administration were 7.1 ± 1.6 and 9.4 ± 3.6 ,ug/ml for the 20 and 40 mg/kg doses, respectively. During the first 24 h after administration, an average of 80% of the intravenous doses and less than 25% of the oral doses were recovered in the urine.Fosfomycin, a broad-spectrum bactericidal agent which inhibits the cell wall synthesis of both gram-positive and gram-negative bacteria (4,8,17), was discovered in Streptomyces fradiae fernentation broths (15).Although pharmacokinetic properties of fosfomycin have been studied in humans (1, 12) after intravenous and oral administration of 250-or 500-mg doses, the pharmacokinetics of larger doses employed therapeutically have not been investigated.The work reported here was undertaken specifically (i) to describe the pharnacokinetics of single relatively larger intravenous and oral doses of fosfomycin and (ii) to utilize these pharmacokinetic data to determine patient dosage schedules and methods of administration. MATERIALS AND METHODSHuman volunteers. Seven adult male volunteers participated in this study after informed written consent had been obtained. Their ages ranged from 25 to 56 years (mean ± standard deviation, 36.3 ± 12.3 years), and their body weight ranged from 45 to 70 kg (57.9 ± 7.0 kg). Prestudy physical examination and pre-and postdrug laboratory findings were normal. No volunteer had a history of allergy to antibiotics or other drugs. None had taken any drug during the month before the investigational period.Dosage. Fosfomycin disodium (lot CS-906; Meiji Seika Research Laboratories, Tokyo, Japan) dissolved in 0.9% saline was administered intravenously at a concentration of 100 mg/ml. Fosfomycin calcium salt (lot FOMDHT 2; Meiji Seika Research Laboratories) was administered orally.Experimental design. Each of the seven volunteers received fosfomycin disodium salt intravenously over 5 min at doses of 20 and 40 mg (potency) per kg. The same volunteers also received fosfomycin calcium salt orally at doses of 20 and 40 mg (potency) per kg. The oral dose was followed by the ingestion of 100 to 120 ml of water. Treatments were randomized and delivered in a crossover fashion, with 2-week intervals separating the respective doses. Subjects fasted overnight before each study; food was also withheld for 2 h after dosage. Blood samples (5 ml each) were drawn from an arm vein at 0 (1 min after the completion of injection), 0.25, 0.5, 1, 2, 4, 6, and 8 h after intravenous administrati...

Fosfomycin

“…In a study comparing the pharmacokinetic (PK) properties of fosfomycin trometamol and fosfomycin calcium, mean peak serum concentrations following a single 2-g dose of fosfomycin trometamol were found to be 2-to 4-fold higher than those obtained after a single 3-g dose of fosfomycin calcium (171). The reason for this observation is that fosfomycin calcium is hydrolyzed and thus inactivated by gastric acid (172)(173)(174).…”

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers

“…fosfomycin as a bolus over 5 min (19). The observed C max after the 1-g dose was 132.1 Ϯ 31.8 g/ml, while V, AUC 0 -∞ , CL, and CL R were 0.34 Ϯ 0.08 liters/kg, 167.9 Ϯ 26.4 g · h/ml, 2.08 Ϯ 0.45 ml/min/kg, and 1.74 Ϯ 0.63 ml/min/kg, respectively.…”

Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections

“…The degree of enteral absorption of the tromethamine salt of fosfomycin is higher compared with that of the calcium salt [7]. The latter has Page 4 of 27 A c c e p t e d M a n u s c r i p t relatively low oral bioavailability (12-28%) [8,9] as it is subject to inactivation by hydrolysis in the acidic gastric environment [10]. The oral bioavailability of the tromethamine salt of fosfomycin is ca.…”