Morris Pfeffer

Comparative Pharmacokinetics of Ceforanide (BL-S786R) and Cefazolin in Laboratory Animals and Humans

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties were determined in rats (100 mg/kg), rabbits (30 mg/kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0- to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no significant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.

Clinical Pharmacokinetics and Safety of High Doses of Ceforanide (BL-S786R) and Cefazolin

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t½, 2.8 h), plasma clearance (Clp, 48 ml/min per 1.73 m2), and renal clearance (Cl0−12hr, 47 ml/min per 1.73 m2; tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t½ (1.9 h), area under the plasma concentration-time curve, Clr (60 ml/min per 1.73 m2; tubular secretion, 80%, and glomerular filtration, 20%), or Clp (75 ml/min per 1.73 m2) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 μg/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

Human pharmacokinetics and disposition of sarmoxicillin, a lipophilic amoxicillin prodrug.

Sarmoxicillin, an amoxicillin prodrug, is the methoxymethyl ester of hetamoxicillin. Esterification converted amoxicillin from an amphoteric to a cationic compound and resulted in a 30- to 600-fold increase in lipid partitioning. Oral absorption studies in normal subjects demonstrated that sarmoxicillin was only partially hydrolyzed by nonenzymatic and gut or hepatic first-pass metabolism and that significant quantities of intact ester appeared in the systemic circulation. Sarmoxicillin was converted to amoxicillin in plasma by hydrolysis of the acetone penicinate and the methoxymethyl ester bonds. Significant amoxicillin levels were demonstrated in saliva after administration of sarmoxicillin, but not amoxicillin, over a 250- to 1,000-mg dose range. Differences in the absorption, distribution, or metabolism of amoxicillin were also evident in the lower plasma amoxicillin maximum concentration and area under the curve and longer half-life after sarmoxicillin administration. Differences in the distribution of this lipophilic ester could result in a significant increase in tissue penetration and subsequent therapeutic efficacy of amoxicillin when administered as sarmoxicillin.

Ceforanide kinetics in renal insufficiency

Ceforanide (500 mg) was infused intravenously over 30 min into six normal subjects, 10 nondialysis patients with renal insufficiency, and six hemodialysis patients. Dialysis patients received two ceforanide infusions, one immediately before dialysis and another during an interdialysis period. Sequential plasma samples over 24 to 72 hr were assayed for ceforanide. Peak ceforanide levels (mean = 69 ± 12 μg/ml) and volumes of distribution did not vary with creatinine clearance (Clcr, ml/min/1.73 m2) and both plasma clearance and renal clearance decreased linearly as Clcr decreased. Mean nonrenal clearance (4.6 ± 1.8 ml/min/1.73 m2) did not vary with Clcr. Mean half‐life was 3 hr in the normal subjects, increasing to approximately 25 hr in patients with severe renal insufficiency. Hemodialysis resulted in removal of approximately 21% of the dose of ceforanide. Dosing recommendations for patients with renal insufficiency are provided.

Pharmacokinetics of intramuscular ceforanide in infants, children, and adolescents.

We studied the pharmacokinetics of intramuscular ceforanide in 46 infants, children, and adolescents, ranging in age from 1 month to 17 years. After the subjects were given 20-mg doses of ceforanide per kg, the mean peak plasma concentration was 56.3 microgram/ml (range, 27.0 to 95.0), the mean 8-h level was 5.9 microgram/ml (range, 1.5 to 13.5), and the mean 12-h level was 1.5 microgram/ml (range, 0.2 to 4.2). Ceforanide half-life varied with the ages of the patients: in 1- to 2-year-old children, in half-life was significantly shorter (1.5 h) than in younger or older children. Plasma concentrations at 8 and 12 h after a dose were lowest in 1- to 2-year-old children. There was no relationship between the area under the curve, the volume of distribution, or the body clearance of ceforanide to the ages of the patients. Within 6 h of administration of the drug, a mean of 77.5% of a dose was excreted in urine, and at the end of 12 h, virtually all (93.9%) of the administered dose was recovered in urine samples. The administration of ceforanide every 12 h did not result in drug accumulation. A dose of 20 mg of ceforanide per kg every 12 h is recommended for most pediatric patients. Dosage recommendations for 1- to 2 year-old children are presented.