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Pharmacokinetics of cefotaxime and its active metabolite in children with renal dysfunction
C M Paap1, M C Nahata, M A Mentser
1Wexner Institute for Pediatric Research, Columbus Children's Hospital, Ohio, USA.
Insights
Pediatric cefotaxime (CTX) pharmacokinetics show that renal impairment significantly impacts drug clearance and half-life. Dosage adjustments are recommended for children with reduced kidney function to ensure safe and effective treatment.
Area of Science:
- Pharmacology
- Pediatric Nephrology
Background:
- Cefotaxime (CTX) is a widely used antibiotic in pediatric care.
- Understanding its pharmacokinetic profile in children with varying renal function is crucial for optimizing therapy.
Purpose of the Study:
- To investigate the pharmacokinetics of cefotaxime (CTX) and its metabolite, desacetylcefotaxime (dCTX), in children with different degrees of renal function.
- To determine the impact of renal impairment on CTX and dCTX clearance and elimination half-life.
Main Methods:
- 19 children (7-16 years) were stratified into three groups based on 24-h urinary creatinine clearance (CLCR).
- A single intravenous dose of CTX (50 mg/kg) was administered.
- Blood and urine samples were analyzed for CTX and dCTX using high-performance liquid chromatography.
- Safety was monitored via pre- and poststudy blood chemistries and urinalysis.
Main Results:
- Total body clearance and renal clearance of CTX decreased significantly with decreasing renal function (CLCR).
- The elimination half-life and fraction of CTX non-renally cleared increased as renal function declined.
- Renal clearance and elimination half-life of dCTX were also significantly affected by CLCR, with higher concentrations and longer times to reach peak levels in patients with impaired renal function.
- CTX volume of distribution at steady state remained unaffected by renal disease.
Conclusions:
- Renal impairment significantly alters cefotaxime and desacetylcefotaxime pharmacokinetics in children.
- Dosage reductions of 25-50% for moderate renal impairment and 50-75% for severe renal impairment are recommended.
- These adjustments are essential for maintaining therapeutic efficacy and preventing potential toxicity in pediatric patients 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 (CLCR) values: group I, CLCR greater than 80 ml/min/1.73 m2 (n = 7); group II, CLCR from 30 to 80 ml/min/1.73 m2 (n = 6); and group III, CLCR less than 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 less than 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 less than 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 less than 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 less than 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 CLCR. 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 (CLCR from 30 to 80 ml/min/1.73 m2) and 50 to 75% in children with severe renal impairment (CLCR < 30 ml/min/1.73 m2) are recommended.