Pharmacokinetics of fosmidomycin, a new phosphonic acid antibiotic

Abstract

The pharmacokinetics offosmidomycin was investigated in animals and humans after parenteral and oral dosing. In dogs the serum concentration was 54.8 ,ug/ml at 0.25 h after an intravenous dose of 20 mg/kg, and the half-life was 1.14 h. Peak concentration was 41.4 ;ig/ml after an intramuscular dose of 20 mg/kg and 16.6 ,g/ ml after an oral dose of 40 mg/kg. In volunteers, the serum concentration 0.25 h after dosing was 157 jig/ml after an intravenous dose of 30 mg/kg, 12.3 ,ug/ml after an intramuscular dose of 7.5 mg/kg, and 2.45 j,g/ml after an oral dose of 500 mg. More than 90% of the given dose was excreted in the 24-h urine in rats and dogs after parenteral dosing with 20 mg/kg. The 24-h urinary recovery was 45.8% of the given dose in rats after oral dosing with 100 mg/kg and 37.8% in dogs after oral dosing with 40 mg/kg. In volunteers 85.5% of the intravenous dose (30 mg/kg), 66.4% of the intramuscular dose (7.5 mg/kg), and 26.0% of the oral dose (500 mg) were excreted unchanged in the 24-h urine. In the multiple-dose study, there was no accumulation of fosmidomycin in the serum even after 21 consecutive intramuscular dosings of 1 g every 6 h or 29 consecutive 0.5-h drip infusions of 2 g every 6 h. Biliary excretion was extremely low in rats. Fosmidomycin was well distributed to the tissues of rats after parenteral and oral dosing. The lymph concentrations in dogs were nearly the same as serum concentrations. Serum protein binding was low (4% or less) to mouse, rat, dog, and human serum.

Estimation of Biliary Excretion of Foreign Compounds Using Properties of Molecular Structure

“…Abou-El-Makarem and his colleagues examined this possibility by tying up the renal pedicles in rats, so that clearance by the kidney was prevented, and the results indicated that when clearance by the kidney is prevented, biliary excretion increased by 10% (12). Fosmidomycin has a short half-life of 1.7 h and is rapidly cleared by the kidneys (43). It is a small molecular weight polar agent which may not be cleared in high quantities through bile according to the molecular weight threshold hypothesis.…”

Synthesis and Antiplasmodial Activity of Highly Active Reverse Analogues of the Antimalarial Drug Candidate Fosmidomycin

“…[5,8] Various research groups are involved in the design of novel DXR inhibitors. [3] Molecular field analyses, as well as crystallographic studies, could already contribute in defining structural requirements for the development of potent DXR inhibitors.…”

Determination of fosmidomycin in human serum and urine by capillary electrophoresis

“…Clinical studies with a combination of fosmidomycin and clindamycin, which was shown to act synergistically, are currently ongoing [7][8][9]. In previous pharmacokinetic studies, a microbiological assay with Enterobacter cloacae as test organism was used for the determination of fosmidomycin in biological fluids [10]. For the current studies, a more convenient and reliable assay is required in order to monitor the efficiency of the dose regimen and to optimize the therapy.…”