Single-dose pharmacokinetics of ceftibuten (SCH 39720) in infants and children

Abstract

Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12-to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cm,.) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (±standard deviations) were as follows: apparent elimination half-life, 2.0 + 0.5 h; mean residence time, 3.9 ± 1.1 h; apparent steady-state volume of distribution, 0.4 ± 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 ± 0.9 m/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to c5 years of age (3.1 ± 1.1 ml/min/kg) than in children >10 years of age (2.0 ± 0.6 ml/min/kg; P < 0.005). The increased CL/F for CFB (3.0 ± 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (6 to 26 months) who were given a single 9.0-mg/kg oral dose. Comparison of renal clearance (1.0 ± 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 + 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.Ceftibuten (CFB; 7432-S, SCH 39720; Schering Corp., Bloomfield, N.J.) is a recently synthesized broad-spectrum oral cephalosporin which has the structural formula 7-3-[(Z)-2-(2-aminothiazol-4-yl)-4-carboxy-2-butenoylamino]-3-cephem-4-carboxylic acid. It exhibits antimicrobial activity against a wide range of gram-negative bacteria and certain gram-positive organisms which frequently represent serious bacterial pathogens in infants and children. In vitro, CFB is highly active against Haemophilus influenzae, Escherichia coli, Klebsiella sp., and Proteus sp. and moderately active against Serratia sp. and ...

Ceftibuten Pharmacokinetics and Pharmacodynamics

“…Secondly, the mean V __ IF of ceftibuten in infants and children is also approximately 2-to 2.5-fold greater than corresponding values reported in adults with normal renal function (Kelloway et al 1991;Nakashima et al 1988a). Thirdly, the apparent CLNR for cis-ceftibuten in paediatric patients when expressed as a percentage of CLIF (52%) [Kearns et al 1991] appears to be higher than that in adults (32%) with creatinine clearances above 80 mllmin (4.8 Lib) [Kelloway et al 1991].…”

“…Comparison of the pharmacokinetic data for ceftibuten in pediatric patients (Kearns et al 1991) with those previously reported from single-dose studies performed in healthy young adults (Kelloway et al 1991;Nakashima et al 1988a;Wise et al 1990) revealed potential developmental differences in the disposition of ceftibuten. First, the mean CLIF in children who are younger than 5 years of age is approximately 2.5-to 3.0-fold greater than values reported from adult studies (Kelloway et al 1991;Nakashima et al 1988a).…”

“…This finding was corroborated by a statistically significant (p < 0.005) inverse correlation between age and both the CLIF (r = 0.54) and elimination rate constant (r = 0.62) for ceftibuten. Further supportive evidence was gained by performing a second study of ceftibuten pharmacokinetics in 11 infants (age 1.2 ± 0.5 years) [Kearns et al 1991]. In this study, CLIF was 3.0 ± 0.5 ml/min/kg (0.18 ± 0.03 L/h/kg).…”

“…This technique is sufficiently sensitive and specific for use in pharmacokinetic analysis, and allows for the reproducible quantification of both cis-and trans-isomers of ceftibuten over a concentration range of 0.1 to 20 mglL in serum and 1 to 200 mgIL in urine. Other investigators have also used HPLC techniques for quantification of ceftibuten in biological matrices to study the pharmacokinetic profile of the drug (Barr et al 1991;Kearns et al 1991;Kelloway et al 1991;Nakashimaetal. 1988a;Wiseetal.…”

Concentrations of Ceftibuten in Bronchial Secretions

“…Quantitation of ceftibuten in duplicate of both sc rum and bronchial secretion was performed by highperformance liquid chromatography (HPLC) accord ing to the method described by Kearns et al [14] with slight modifications. Samples (400 ml) were mixed with 20 ml of internal standard (acyclovir 100 mg/ml) and 600 ml of acetonitrile (Bracco, Milan, Italy).…”