Pharmacokinetic properties of new oral cephalosporins

Abstract

Summary New second- and third-generation cephalosporins which are on the market or in advanced clinical development will be briefly characterized with regard to their pharmacokinetic properties: cefdinir, cefetamet pivoxil, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, ME-1207 and S-1108. They can be divided into those absorbed as the parent compound and others absorbed in the form of ester prodrugs. Most of these new compounds are aminothiazole/oxime type cephalosporins. Although their kinetic behaviour is probably mostly structure-related, individual pH-dependent water solubility as well as lipophilicity characteristics exert in addition considerable differences. Typically observed kinetic parameter data: 40 to 70 % bioavailability with plasma peak concentrations at 2 to 4 h, low to moderate protein binding (20–40 %), distribution into the extracellular water space, unbound drug clearance (150–200 ml/min) almost exclusively by glomerular filtration, low non-renal clearance (5–20 % of total clearance), half-lives of about 2 h. Administration with food increases the bioavailability of all prodrug ester cephalosporins (by up to 70 %). Cefprozil and S-1108 present higher (up to 400 ml/min), cefixime lower unbound drug clearance (80 ml/min). Ceftibuten and cefixime show considerably high contributions of hepatic clearance (40 and 60 %). Antacids reduce the bioavailability of cefpodoxime proxetil, cefuroxime axetil and S-1108 (by up to 40 %). As expected, similar changes in the kinetic parameters with the degree of renal dysfunction are obtained for all compounds, to be easily managed by dose adjustments related to creatinine clearance. In liver disease, cefixime reveals approx. 2-fold increased elimination half-life (6 h) as a consequence of reduced hepatic clearance mechanisms.