Pharmacokinetics of cefotaxime and its active metabolite in children with renal dysfunction

Abstract

We studied cefotaxime (CTX) and desacetylcefotaxime (dCTX) pharmacokinetics in 19 children (ages, 7 to 16 years) with various degrees of renal function. The patients were stratified into three groups according to 24-h urinary creatinine clearance (CL(CR)) values: group I, CL(CR) > 80 ml/min/1.73 m2 (n = 7); group II, CL(CR) from 30 to 80 ml/min/1.73 m2 (n = 6); and group III, CL(CR) < 30 ml/min/1.73 m2 (n = 6). A single 50-mg/kg dose of CTX was given intravenously to each patient after which blood and urine samples were collected and analyzed for CTX and dCTX by high-performance liquid chromatography. Safety was assessed by pre- and poststudy blood chemistries and urinalysis. The mean values for total body clearance of CTX for groups I, II, and III were 158.1 ± 38.8, 118.3 ± 50.8, and 84.8 ± 11.7 ml/min/1.73 m2, respectively (P < 0.01). Renal clearance also decreased across groups, I, II, and III, with values of 77.5 ± 20.2, 41.3 ± 18.5, and 11.4 ± 7.7 ml/min/1.73 m2 respectively (P < 0.0001). Both the CTX fraction nonrenally cleared and elimination half-life increased with decreasing renal function. The CTX volume of distribution at steady state was not affected by renal disease. The renal clearance values of dCTX were 146.4 ± 71.4, 64.5 ± 32.1, and 14.4 ± 8.7 ml/min/1.73 m2 for groups I, II, and III, respectively (P < 0.0004). Elimination half-life values were 2.04 ± 0.39, 3.87 ± 1.93, and 6.19 ± 3.22 h for the respective groups (P < 0.006). Both the maximum concentration of dCTX in plasma and time to reach the maximum concentration of dCTX in plasma were increased with decreased CL(CR). The results of this study indicate that dosage adjustment may be necessary for CTX in children with renal dysfunction. On the basis of the pharmacokinetics and antimicrobial activities of the parent drug and its metabolite, dosage reductions of 25 to 50% in children with moderate renal impairment (CL(CR) from 30 to 80 ml/min/1.73 m2) and 50 to 75% in children with severe renal impairment (CL(CR) < 30 ml/min/1.73 m2) are recommended.