Fosmidomycin: a new phosphonic acid antibiotic. Part I: Phase I tolerance studies

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, in average, about 30% (in comparison with fosfomycin which is, in average, about 11% only). The absorption seems to be slow and moderate. In single dose studies, the mean peak serum concentrations were 2.45 micrograms/ml and 12.3 micrograms/ml after 500 mg oral 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 micrograms/ml at 0.25 h. The serum halflives 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 micrograms/ml were recorded at steady state. The serum protein binding could be found in man less than 1%. Unmetabolized fosmidomycin was the only bioactive substance found in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)