CEFETAMET PIVOXIL CLINICAL PHARMACOKINETICS

Cefetamet pivoxil is an orally absorbed prodrug ester of the microbiologically active cephalosporin, cefetamet. The prodrug ester is completely hydrolysed to the active compound cefetamet on its first pass through the gut wall, the liver or both. Cefetamet is classified as a third generation cephalosporin with excellent activity against streptococci, Enterobacteriaceae, Neisseria and Haemophilus species. It has enhanced stability against beta-lactamases compared with penicillins and first and second generation cephalosporins. The antibacterial spectrum is comparable with that of cefotaxime except for its poor activity against staphylococci. Following a 20-minute zero-order intravenous infusion, cefetamet had a rapid distribution phase followed by a monoexponential decline. The average pharmacokinetic parameters from 152 healthy volunteers were: total body clearance 136 ml/min (8.16 L/h); renal clearance 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 elimination half-life 2.2 hours; 88% of the dose recovered in the urine. Cefetamet is not extensively bound to plasma proteins. Consequently, these data indicate that cefetamet is predominantly eliminated unchanged by the 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. Results following ascending intravenous doses of cefetamet in healthy young male volunteers demonstrated that the pharmacokinetics of intravenous cefetamet are independent of the dose. The absolute bioavailability of cefetamet tablets following oral cefetamet pivoxil administration is enhanced by the presence of food. Under fed conditions, 50 to 60% of the final oral dose is absorbed into the systemic circulation. This food effect is observed when cefetamet pivoxil is administered within 1 hour of a meal. Food also produces a slight delay in the time to reach peak plasma concentrations of this drug. Changes in fluid volume intake with cefetamet pivoxil administration have no effect on the bioavailability of this drug. Similar absorption characteristics have been observed for all of the tablet dosage formulations studied during clinical development. The absolute bioavailability of the final syrup dosage formulation was between 38 and 47%. Little improvement in the bioavailability of this preparation has been observed with food. The absorption and disposition of cefetamet in human subpopulations [i.e. children, 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 elimination of this drug. Dosage adjustments are recommended for patients with renal disease who have creatinine clearance values below 40 ml/min/1.73m2 (2.4 L/h/1.73m2). Standard dosages of 500mg every 12 hours should for most of the dosage interval produce unbound plasma concentrations above the minimum concentrations required to kill 90% of susceptible bacterial strains (MIC90).