Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design

Leroux, Stéphanie; Turner, Mark A.; Guellec, Chantal Barin‐Le; Hill, H; Anker, Johannes N. van den; Kearns, Gregory L.; Jacqz-Aigrain, Évelyne; Zhao, Wei

doi:10.1007/s40262-015-0291-1

Cited by 72 publications

(73 citation statements)

References 16 publications

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“…However, as shown in our previous study (7), it might be not powerful enough to identify all significant covariates and could underpredict variability. The posterior dosage adaptation based on therapeutic drug monitoring might provide additional benefits to optimize individual antimicrobial therapy.…”

Section: Figmentioning

confidence: 77%

“…The use of an opportunistic pharmacokinetic sampling design facilitated patient inclusion and provided dosing recommendations similar to those from a predetermined (i.e., scheduled) pharmacokinetic sampling design (7). However, as shown in our previous study (7), it might be not powerful enough to identify all significant covariates and could underpredict variability.…”

Section: Figmentioning

confidence: 98%

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A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Leroux

Roué

Gouyon

et al. 2016

Antimicrob Agents Chemother

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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. C efotaxime is one of the most frequently prescribed antibiotics in neonates (1). This third-generation cephalosporin is mainly used in the treatment of neonatal sepsis (2) and meningitis caused by Gram-negative bacteria. Because of the high rates of morbidity and mortality (3), the optimal use of cefotaxime is essential in neonatal infection management. However, the dosing regimens routinely used in clinical care vary considerably. As reported in our previous study, 25 different dosage regimens of cefotaxime were identified in the French neonatal intensive care unit (NICU) network, with median daily doses varying from 75 mg/kg of body weight/day to 180 mg/kg/day among NICUs (4). This huge variation can be partly explained by the different dosage recommendations available in reference textbooks and published guidelines (1). It also highlights the need for powerful pharmacokinetic (PK) data for neonates. As recently reviewed by Pacifici et al. (5), the pharmacokinetics of cefotaxime in neonates were mainly studied in the 1980s with a limited number of patients. The study design and analysis method limited the power to determine a precise dose of cefotaxime derived from pharmacokinetic data, as the quantitative impacts of covariates (i.e., maturation, organ function) on dose were not fully assessed. The simplification of the impacts of covariates could lead to signific...

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Section: Figmentioning

confidence: 77%

Section: Figmentioning

confidence: 98%

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Leroux

Roué

Gouyon

et al. 2016

Antimicrob Agents Chemother

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“…Started in 2011, the ongoing POPS trial is enrolling a total of 3000 children to evaluate the PK of >30 understudied drugs, including trimethoprim sulfamethoxazole, clindamycin, ampicillin, and others. Similar European initiatives are also capitalizing on opportunistic study designs to characterize the PK of understudied drugs (eg, ciprofloxacin) …”

Section: Clinical Trial Optimizationmentioning

confidence: 99%

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Balevic

Cohen‐Wolkowiez

2018

The Journal of Clinical Pharma

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Almost half of recent pediatric trials failed to achieve labeling indications, due in large part to inadequate study design. Therefore, innovative study methods are crucial to optimize trial design while also reducing the potential harms inherent with drug investigation. Several methods exist to optimize the amount of pharmacokinetic (PK) data collected from the smallest possible volume and with the fewest number of procedures, including the use of opportunistic and sparse sampling, alternative and non-invasive matrices, and micro-volume assays. In addition, large research networks using master protocols promote collaboration, reduce regulatory burden, and increase trial efficiency for both early- and late-phase trials. Large pragmatic trials that leverage electronic health records can capitalize on central management strategies to reduce costs, enroll patients with rare diseases on a large scale, and augment study generalizability. Further, trial efficiency and safety can be optimized through Bayesian adaptive techniques that permit planned protocol changes based on analyses of prior and accumulated data. In addition to these trial design features, advances in modeling and simulation have paved the way for systems-based and physiologically-based models that individualize pediatric dosing recommendations and support drug approval. Lastly, given the low prevalence of many pediatric diseases, collecting de-identified genetic and clinical data on a large scale is a potentially transformative way to augment clinical pharmacology research in children.

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“…The timing and frequency of such blood samples is, of course, unpredictable. The scavenged sampling approach and a more traditional fixed sampling approach were compared with respect to ciprofloxacin pharmacokinetics in neonates and infants <3 months of age . Similar to the cefepime study above, 4 fixed‐sampling groups (4 samples/group) with staggered times were used, depending on whether the drug was infused twice or three times daily.…”

Section: Academic Perspectivementioning

confidence: 99%

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

Neely

Bayard

Desai

et al. 2018

The Journal of Clinical Pharma

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Pediatric clinical pharmacology now encompasses a wide range of activities, including drug pharmacokinetic and pharmacodynamic modeling and simulation, also known as pharmacometrics. Pediatric clinical pharmacologists may be physicians but are more likely to be pharmacists or PhD scientists, and pediatric clinical pharmacology today is largely a research specialty rather than a subspecialty for direct patient care. Pharmacometrics, including “top‐down” population modeling and “bottom‐up” physiologically based pharmacokinetic modeling, has become an indispensable tool for pharmaceutical industry scientists, government regulators, academic researchers, and even a handful of patient‐oriented practitioners. This review summarizes the application of pharmacometrics within each of these domains and predicts future trends of further applications across the spectrum of pediatric clinical pharmacology from drug development to patient care.

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Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design

Abstract: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

Cited by 72 publications

References 16 publications

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

A Population and Developmental Pharmacokinetic Analysis To Evaluate and Optimize Cefotaxime Dosing Regimen in Neonates and Young Infants

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

Pharmacometric Modeling and Simulation Is Essential to Pediatric Clinical Pharmacology

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