FOSMIDOMYCIN, A NEW PHOSPHONIC ACID ANTIBIOTIC .2. HUMAN PHARMACOKINETICS .1. PRELIMINARY EARLY PHASE-II A CLINICAL-STUDIES .2.

  • 1 January 1985
    • journal article
    • research article
    • Vol. 23  (10) , 521-528
Abstract
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. [per os] for 7 days. The gastrointestinal absorption rate after the oral dosing of 500 mg is in general about 20-40% which can be calcualted to be in average about 30% (in comparisn 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 .mu.g/ml and 12.3 .mu.g/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 .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 8.55%, 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 34.0-3.5.5 .mu.g/ml were recorded at steady state. The serum protein binding could be found to be less than 1% in man. Unmetaboized 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 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.

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