PHARMACOKINETICS OF L-749,345, A LONG-ACTING CARBAPENEM ANTIBIOTIC, IN PRIMATES

L-749,345 is a carbapenem antibiotic, currently in phase II clinical t rials, which possesses a broad antibacterial spectrum and extended hal f-life, The time courses of levels of the drugs in plasma and urinary recovery were evaluated for L-749,345, imipenem-cilastatin (IPM), and ceftriaxone (CTX) in male rhesus monkeys (Macaca mulatta) and a chimpa nzee (Pan troglodytes). The chimpanzee pharmacokinetics was predictive of human results and indicated a compound that was superior to IPM an d approached CTX in its ability to persist in the circulation, Levels of binding to protein, in the range of clinically relevant concentrati ons in serum, are virtually equivalent for L-749,345 and CTX in humans , Results of a crossover bioassay versus those of a high-pressure liqu id chromatography assay of l-g human samples showed that there were no bioactive metabolites of L-749,345, The extended half-life at elimina tion phase of L-749,345 allows consideration of single daily dosing, I n contrast to results with IPM, the improved stability of L-749,345 wi th respect to hydrolysis by the renal dehydropeptidase I (0.25 times t he rate of IPM) results in urinary recovery sufficient for the drug's use as a single agent.