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Pharmacokinetics of imipenem-cilastatin in neonates
Insights
This study investigated the pharmacokinetics of imipenem-cilastatin in newborns, finding that cilastatin had higher plasma concentrations and longer half-lives than imipenem. Neonatal pharmacokinetics resembled adults with renal insufficiency.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Drug Metabolism
Background:
- Imipenem-cilastatin is a critical antibiotic combination used in various infections.
- Understanding its pharmacokinetic profile in neonates is crucial for safe and effective dosing.
- Renal dehydropeptidase I inhibition by cilastatin is key to imipenem's efficacy.
Purpose of the Study:
- To characterize the pharmacokinetics of imipenem and cilastatin when coadministered intravenously to newborns.
- To compare the plasma concentrations, half-lives, and clearance of imipenem and cilastatin in this population.
- To assess drug accumulation after multiple doses and compare neonatal pharmacokinetics to adult data.
Main Methods:
- Intravenous coadministration of imipenem-cilastatin (1:1 ratio) to 30 newborns.
- Single doses (10, 15, 20 mg/kg) and multiple doses (20 mg/kg every 12h) were administered.
- Plasma and urinary concentrations were measured, and pharmacokinetic parameters were analyzed using a one-compartment model.
Main Results:
- Plasma concentrations were dose-proportional; cilastatin exhibited higher concentrations and longer half-lives (3.9–6.3 h) than imipenem (1.7–2.4 h).
- Cilastatin's plasma clearance was approximately one-quarter of imipenem's, despite higher urinary concentrations of cilastatin.
- No significant drug accumulation occurred with repeated dosing; intersubject variability was noted, particularly for cilastatin.
Conclusions:
- Neonatal pharmacokinetics of imipenem-cilastatin resemble those in adults with moderate to severe renal insufficiency.
- The distinct pharmacokinetic profiles of imipenem and cilastatin in neonates warrant careful consideration.
- Further research is recommended to elucidate the effects of enzyme inhibition in neonates and optimize dosing strategies.
Abstract:
Imipenem and its renal dehydropeptidase I inhibitor, cilastatin, were coadministered intravenously in a 1:1 ratio to 30 newborns. Five infants each received single doses of 10, 15, or 20 mg/kg of both drugs. Concentrations in plasma were proportional to the administered dose, and cilastatin achieved consistently higher concentrations than did equivalent doses of imipenem because of its smaller volume of distribution. The pharmacokinetics of both drugs were best described by a one-compartment model. The plasma half-lives of imipenem were 1.7 to 2.4 h, whereas those of cilastatin were 3.9 to 6.3 h. The plasma clearance of cilastatin was approximately one-quarter of that of imipenem in the dose range tested. The urinary concentrations of imipenem were 50% of those of cilastatin despite its higher clearance from plasma. Fifteen additional newborns received five to eight doses of imipenem-cilastatin at 20 mg/kg per dose every 12 h. There was no accumulation of either drug in plasma after repeated administrations, and the mean concentrations in plasma were similar when measured on the first and last days of the multiple-dose study. There was marked intersubject variability, more so for cilastatin. The pharmacokinetics of both drugs in neonates resembled those observed in adults with moderate to severe renal insufficiency. Because the effects of enzyme inhibition on neonates are unknown, additional studies with imipenem-cilastatin (primaxin) are recommended.