title: A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants.
abstract: Cefotaxime is one of the most frequently prescribed antibiotics for the treatment of Gram-negative bacterial sepsis in neonates. However, the dosing regimens routinely used in clinical practice vary considerably. The objective of the present study was to conduct a population pharmacokinetic study of cefotaxime in neonates and young infants in order to evaluate and optimize the dosing regimen. An opportunistic sampling strategy combined with population pharmacokinetic analysis using NONMEM software was performed. Cefotaxime concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Developmental pharmacokinetics-pharmacodynamics, the microbiological pathogens, and safety aspects were taken into account to optimize the dose. The pharmacokinetic data from 100 neonates (gestational age [GA] range, 23 to 42 weeks) were modeled with an allometric two-compartment model with first-order elimination. The median values for clearance and the volume of distribution at steady state were 0.12 liter/h/kg of body weight and 0.64 liter/kg, respectively. The covariate analysis showed that current weight, GA, and postnatal age (PNA) had significant impacts on cefotaxime pharmacokinetics. Monte Carlo simulations demonstrated that the current dose recommendations underdosed older newborns. A model-based dosing regimen of 50 mg/kg twice a day to four times a day, according to GA and PNA, was established. The associated risk of overdose for the proposed dosing regimen was 0.01%. We determined the population pharmacokinetics of cefotaxime and established a model-based dosing regimen to optimize treatment for neonates and young infants.
authors: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.|EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France.|Neonatal Intensive Care Unit, CHU de Rennes, Rennes, France.
authors: Stéphanie
authors: S
authors: Leroux
authors: Neonatal Intensive Care Unit, CHU de Brest, Brest, France.
authors: Jean-Michel
authors: JM
authors: Roué
authors: Neonatal Intensive Care Unit, Centre d'Etudes Périnatales de l'Océan Indien (EA7388), CHU de la Réunion, Réunion, France.
authors: Jean-Bernard
authors: JB
authors: Gouyon
authors: Neonatal Intensive Care Unit, Hôpital Robert Debré, APHP, Paris, France.
authors: Valérie
authors: V
authors: Biran
authors: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.
authors: Hao
authors: H
authors: Zheng
authors: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France.|EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France.|Clinical Investigation Center CIC1426, INSERM, Paris, France.
authors: Wei
authors: W
authors: Zhao
authors: Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France evelyne.jacqz-aigrain@rdb.aphp.fr.|EA7323, Université Paris Diderot-Université Paris Descartes, Paris, France.|Clinical Investigation Center CIC1426, INSERM, Paris, France.
authors: Evelyne
authors: E
authors: Jacqz-Aigrain
mesh_terms: D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001835:Body Weight; D002439:Cefotaxime / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D005865:Gestational Age; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007362:Intensive Care Units; D008297:Male; D015233:Models, Statistical; D009010:Monte Carlo Method; D018805:Sepsis / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D053719:Tandem Mass Spectrometry
chemical_list: D000900:Anti-Bacterial Agents; D002439:Cefotaxime