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

Abstract

The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were evaluated after a single dose in 28 healthy adult subjects. Subjects received a single 1-h i.v. infusion of 1 g and 8 g fosfomycin disodium and a single dose of 3 g oral fosfomycin tromethamine in a phase I, randomized, open-label, three-period crossover study. Serial blood and urine samples were collected before and up to 48 h after dosing. The mean pharmacokinetic parameters Ϯ standard deviations of fosfomycin in plasma after 1 g and 8 g i.v., respectively, were the following: maximum clearance of drug in serum (C max ), 44.3 Ϯ 7.6 and 370 Ϯ 61.9 g/ml; time to maximum concentration of drug in serum (T max ), 1.1 Ϯ 0.05 and 1.08 Ϯ 0.01 h; volume of distribution (V), 29.7 Ϯ 5.7 and 31.5 Ϯ 10.4 liters; clearance (CL), 8.7 Ϯ 1.7 and 7.8 Ϯ 1.4 liters/h; renal clearance (CL R ), 6.6 Ϯ 1.9 and 6.3 Ϯ 1.6 liters/h; area under the concentrationtime curve from 0 to infinity (AUC 0 -∞ ), 120 Ϯ 28.5 and 1,060 Ϯ 192 g·h/ml; and half-life (t 1/2 ), 2.4 Ϯ 0.4 and 2.8 Ϯ 0.6 h. After oral administration, the parameters were the following: C max , 26.8 Ϯ 6.4 g/ml; T max , 2.25 Ϯ 0.4 h; V/F, 204 Ϯ 70.7 liters; CL/F, 17 Ϯ 4.7 liters/h; CL R , 6.5 Ϯ 1.8 liters/h; AUC 0 -∞ , 191 Ϯ 57.6 g · h/ml; and t 1/2 , 9.04 Ϯ 4.5 h. The percent relative bioavailability of orally administered fosfomycin was 52.8% in relation to the 1-g i.v. dose. Approximately 74% and 80% of the 1-g and 8-g i.v. doses were excreted unchanged in the urine by 48 h compared to 37% after oral administration, with the majority of this excretion occurring by 12 h regardless of dosage form. No new safety concerns were identified during this study. The results of this study support further investigation of i.v. fosfomycin in the target patient population, including patients with complicated urinary tract infections and pyelonephritis.

Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide

“…8 A review of the FDA Adverse Events Reporting System for fosfomycin also noted similar aminotransferase level elevation rates (1-2%). 108 Other events noted in a phase I open-label trial of an IV fosfomycin 8-g dose were bradycardia (28.6%), defined as heart rate of 54 beats/minute or lower and hypocalcemia (10.7%) 43 These treatment-related adverse events resolved by the end of the study with the exception of one case of mild hypocalcemia and one case of anemia. No other laboratory abnormalities were observed in this study.…”

“…Intravenous fosfomycin pharmacokinetics (PK) has been studied in various phase I and II trials over the last several decades . More recent evaluations of IV fosfomycin 1‐ and 8‐g doses were performed in a phase I trial of 27 healthy adults (Table ) . The average age of subjects was 27 years, 40% were male, and mean creatinine clearance (Cl cr ) was 140 ml/minute.…”

“…41,42 More recent evaluations of IV fosfomycin 1-and 8-g doses were performed in a phase I trial of 27 healthy adults (Table 4). 43 The average age of subjects was 27 years, 40% were male, and mean creatinine clearance (Cl cr ) was 140 ml/minute. When 1 g IV was administered, the drug exhibited a maximum concentration (C max ) of 44.3 AE 7.6 lg/ml, area under the concentration-time curve (AUC) from time zero to the time of the last measurable concentration (AUC last ) of 117 AE 27.7 lgÁhour/ml, and elimination half-life (t 1/2 ) of 2.4 AE 0.4 hours.…”

Unexpected activity of oral fosfomycin against resistant strains ofEscherichia coliin murine pyelonephritis

“…In the current era of increasing prevalence of antibiotic resistance, fosfomycin has attracted renewed interest for the treatment of infections caused by multidrug-resistant pathogens, and especially UTIs. Indeed, it has a broad-spectrum antimicrobial activity and a favorable safety profile (4, 5). Fosfomycin-tromethamine, a soluble salt with improved bioavailability over fosfomycin, is currently recommended in single-dose as the first-line drug for the treatment of uncomplicated lower UTIs in Europe (6) and in the United States (7).…”

“…Furthermore, Martin-Gutierrez et al recently demonstrated that anaerobiosis and acidic pH values in urine decreased fosfomycin MICs in strains harboring chromosomal resistance mutations (12). Finally, it has been previously shown that high concentrations (1000-4000 μg/ml) were achieved in urine after oral administration of 3 g of fosfomycin-tromethamine in humans and remained above 100 μg/ml for at least 30-40h (13), but data on concentrations in kidneys are scarce.…”