Pharmacokinetics of ceforanide in patients with end stage renal disease on hemodialysis.

The pharmacokinetics of ceforanide were evaluated in 11 patients with end stage renal disease (creatinine clearance less than 5 ml/min). A single intravenous dose of 750 mg/m2 produced peak plasma concentrations of 123 +/- 29 microgram/ml. The plasma half-life (T 1/2) of the drug was 19.1 +/- 2.5 h. A 5.5 h hemodialysis session removed 53% of the drug and reduced the T 1/2 to 5 +/- 0.7 h. Plasma concentrations greater than 10 microgram/m2 were maintained without adverse effects with a 1.5-g/m2 dose administered three times a week for 2 weeks.

dose administered three times a week for 2 weeks.
Ceforanide is a new semisynthetic cephalosporin with a broad antibacterial spectrum (4,7). It is at least as active as other available cephalosporins against strains of Escherichia coli, Klebsiella, Proteus mirabilis, and Salmonella (1,4,7). Comparative testing with cefamandole, cephalexin, cefoxitin, cephalothin, and cephapirin in vitro discloses that ceforanide is less potent against gram-positive cocci (1,7), but these observable differences may not be a practical problem in the clinical setting where in vitro mean inhibitory concentrations are exceeded severalfold (4). Like other cephalosporins, ceforanide is predominantly eliminated by the kidney and may accumulate with decreasing renal function (7). The purpose of this study is to describe the pharmacokinetics of ceforanide in patients with end stage renal disease while on hemodialysis (HD) and in the interdialytic period.
MATERIALS AND METHODS Patient population. Seven male and four female volunteers, ages 26 to 71 years, participated in this study. AU patients had a creatinine clearance of <5 ml/min and were considered clinically stable and free of active intercurrent diaease. Five were hospitalized for revision of vascular access sites; the others were outpatients. The patients had been undergoing HD treatments for periods ranging from 1 month to 5.5 years. All received vitamins and antacids, and none received antibiotics for 3 weeks before or during the study. Complete blood count, serum glutamic oxalacetic tra nase, alkaline phosphatase, bilirubin, and Coomb's tests were performed before ceforanide was administered, after 1 week, and after completion of ceforanide treatment. Recirculating single-pass dialysis machines with varying surface areas and dialysate flow rates were used (Table 1). All HD sessions lasted 5.5 h.
Interdialysis pharmacokinetics. Five inpatient volunteers were administered ceforanide, 750 mg/m2 of body surface area, in 150 ml of normal saline intravenously through the blood access site over 10 min starting 30 min before HD was completed. Forearm blood samples were obtained from the vascular access site at 1, 4, 12, 24, and 36 h after the end of HD, and just before the next HD session.
Pharmacokinetics during HD. Six outpatient volunteers received intravenous ceforanide, 750 mg/ m2 of body surface area, diluted in 100 ml of 5% dextrose and water and administered through the vascular access site over a 10-min period. HD was started 30 min later. Blood samples from the arterial and venous sides of the dialyzer and dialysate samples were obtained after 0, 1, 2, 3, 4, and 5.5 h of HD. All dialysate was collected from one of the patients and assayed.
Multiple-dose pharmacokineties. Six outpatient volunteers each received 1.5 g of ceforanide per m2 in 50 ml of normal saline given over 10 min, starting 30 min before the completion of HD, for five consecutive HD sessions spaced at 48 or 72 h apart. Blood samples were obtained from the arterial vascular access just before (trough) and 20 min after (peak) each successive dose. Assay for ceforanide. Blood samples (4 ml) were collected in heparinized vacuum tubes and immediately placed on ice. Plasma was separated within 1 h and frozen until assayed. Dialysate was collected directly into sterile tubes and frozen immediately. Specimens were assayed by the agar plate cup bioassay method using Bacillus subtilis spore suspension (Difco Laboratories, Detroit, Mich.) in a nutrient agar overlay. Antibiotic-free human plasma was the diluent for all specimens except for the dialysate assay, in which antibiotic-free dialysate was used. These methods have been previously described (2,3,6).
where In is the natural logarithm and K. is the exponential elimination rate determined by the leastsquares method.

RESULTS
The T1/2 of ceforanide in patients with end stage renal disease was 19.1 ± 2.5 h in the interdialysis period (Table 2). HD reduced the T1/2 to 5 ± 0.7 h in six other patients (Tables 1   and 3). Of the administred dose, 46% of ceforanide was recovered in the full volume of dialysate collected from one patient (no. 1). Ceforanide, 1.5 g/m2 of body surface area, administered to six patients at the conclusion of