CEFETAMET PIVOXIL CLINICAL PHARMACOKINETICS

Cefetamet pivoxil is an orally absorbed prodrug ester of the microbiol ogically active cephalosporin, cefetamet. The prodrug ester is complet ely hydrolysed to the active compound cefetamet on its first pass thro ugh the gut wall, the liver or both. Cefetamet is classified as a thir d generation cephalosporin with excellent activity against streptococc i, Enterobacteriaceae, Neisseria and Haemophilus species. It has enhan ced stability against beta-lactamases compared with penicillins and fi rst and second generation cephalosporins. The antibacterial spectrum i s comparable with that of cefotaxime except for its poor activity agai nst staphylococci. Following a 20-minute zero-order intravenous infusi on, cefetamet had a rapid distribution phase followed by a monoexponen tial decline. The average pharmacokinetic parameters from 152 healthy volunteers were: total body clearance 136 ml/min (8.16 L/h); renal cle arance 119 ml/min (7.14 L/h); nonrenal clearance 17 ml/min (1.02 L/h); volume of distribution at steady-state 0.29 L/kg; terminal eliminatio n half-life 2.2 hours; 88% of the dose recovered in the urine. Cefetam et is not extensively bound to plasma proteins. Consequently, these da ta indicate that cefetamet is predominantly eliminated unchanged by th e kidney via glomerular filtration with possibly a minor component of tubular secretion. Cefetamet has a relatively small apparent volume of distribution consistent with that of other beta-lactam antibiotics. R esults following ascending intravenous doses of cefetamet in healthy y oung male volunteers demonstrated that the pharmacokinetics of intrave nous cefetamet are independent of the dose. The absolute bioavailabili ty of cefetamet tablets following oral cefetamet pivoxil administratio n is enhanced by the presence of food. Under fed conditions, 50 to 60% of the final oral dose is absorbed into the systemic circulation. Thi s food effect is observed when cefetamet pivoxil is administered withi n 1 hour of a meal. Food also produces a slight delay in the time to r each peak plasma concentrations of this drug. Changes in fluid volume intake with cefetamet pivoxil administration have no effect on the bio availability of this drug. Similar absorption characteristics have bee n observed for all of the tablet dosage formulations studied during cl inical development. The absolute bioavailability of the final syrup do sage formulation was between 38 and 47%. Little improvement in the bio availability of this preparation has been observed with food. The abso rption and disposition of cefetamet in human subpopulations [i.e. chil dren, elderly (<75 years of age), renal impairment, liver disease and patients taking concomitant drugs] have been studied extensively. Only impaired renal function appears to significantly alter the eliminatio n of this drug. Dosage adjustments are recommended for patients with r enal disease who have creatinine clearance values below 40 ml/min/1.73 m2 (2.4 L/h/1.73m2). Standard dosages of 500mg every 12 hours should f or most of the dosage interval produce unbound plasma concentrations a bove the minimum concentrations required to kill 90% of susceptible ba cterial strains (MIC90).