Pharmacokinetic evaluation of fosmidomycin, a new phosphonic acid antibiotic
Kuemmerle, H.P.; Murakawa, T.; De Santis, F.
Chemioterapia International Journal of the Mediterranean Society of ChemoTherapy 6(2): 113-119
1987
ISSN/ISBN: 0392-906X PMID: 3594633 Document Number: 288076
The pharmacokinetics of fosmidomycin in phase I with a total of 127 healthy male volunteers is described through single-and repeated-dose studies using oral and parenteral routes of administration. The study results indicate that fosmidomycin is well tolerated even when given in repeated doses of 8 g/day i.v. for 7 days, 4 g/day i.m. for 5 days, and 4 g/day p.o. for 7 days. The gastrointestinal absorption rate after oral dosing of 500 mg is in general about 20-40%, which can be calculated to be on average about 30% (in comparison with fosfomycin which is on average only about 11%). Absorption seems to be slow and moderate. In the single-dose studies, the mean peak serum concentrations were 2.45 .mu.g/ml and 12.3 .mu.g/ml after 500 mg p.o. and 7.5 mg/kg (ca. 500 mg) i.m. doses respectively. The mean concentration after 15 mg/kg (ca. 2.2 g) i.v. dose was 157 .mu.g/ml at 0.25 h. The serum half-lives were 1.65 h, 1.58 h and 1.87 h after i.v., i.m. and p.o. doses respectively. The recovery rate in urine was 85.5%, 66.4% and 26% after i.v., i.m. and p.o. doses respectively. In repeated-dose studies, no serum accumulation could be observed after 1 g q6h for 5 days, 1 g q6h for 7 days or 2 g q6h for 7 days. Mean peak serum levels of 34.0-35.5 .mu.g/ml were recorded at steady state. The serum protein binding found in man was less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine. Fosmidomycin is a promising and useful antibiotic with higher antibacterial activity and potency than fosfomycin against gram-negative rods. In preliminary and very early phase IIa clinical studies fosmidomycin showed a good profile which has to be confirmed in controlled clinical trials. Further clinical evaluation can be recommended.