PHARMACOKINETICS OF CEFTIBUTEN-CIS AND ITS TRANS-METABOLITE IN HEALTHY-VOLUNTEERS AND IN PATIENTS WITH CHRONIC RENAL-INSUFFICIENCY

The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects. Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CL(CR)). The apparent total body clearance (CL(P)/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CL(CR), 5 to 29 ml/min; group IV) and moderate (CL(CR), 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CL(CR), 50 to 80 ml/min; group II) or normal renal function (CL(CR), > 80 ml/min; group I). A significant correlation was observed between CL(CR) and ceftibuten-cis CL(P)/F. The mean apparent steady-state volume of distribution (V-beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV. V-beta/F was significantly greater in the group V subjects with end-stage renal disease (V-beta/F, 0.39 +/- 0.27 liters/kg). These changes in V-beta/F cannot be separated from possible changes in bioavailability. The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups. The terminal elimination half-life of ceftibuten-trans was significantly and progressively prolonged as CL(CR) declined (2.63 +/- 1.02, 5.37 +/- 1.93, 14.29 +/- 10.84, and 19.46 +/- 9.69 h in groups I, II, III, and IV, respectively). The hemodialysis clearance of ceftibuten-cis was 76.9 +/- 18.0 ml/min, and the fraction of the administered dose of ceftibuten-cis removed during approximately 3 h of hemodialysis was 39 +/- 9%. Ceftibuten dosage adjustments are proposed for subjects with renal insufficiency.