Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology

Barker, Charlotte I. S.; Germovsek, Eva; Hoare, Rollo L.; Lestner, Jodi M.; Lewis, Joanna; Standing, Joseph F.

doi:10.1016/j.addr.2014.01.002

Cited by 33 publications

(26 citation statements)

References 197 publications

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“…Many of the more recently introduced antifungal agents, such as echinocandins and secondgeneration triazoles, have been specifically studied and differentially licensed for use in neonates and children (28)(29)(30)(31). Welldesigned prospective PK-PD studies in clinical settings, in conjunction with modeling and simulation based on preclinical data, are the best tools for establishing equivalent evidence-based optimal dosing regimens for these older agents (32). As in previous observational studies, systemic antifungals were most frequently prescribed for the prevention and treatment of IFI in immunosuppressed children and preterm neonates (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Systemic Antifungal Prescribing in Neonates and Children: Outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study

Lestner

Versporten

Doerholt

et al. 2015

Antimicrob Agents Chemother

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The appropriate use of systemic antifungals is vital in the prevention and treatment of invasive fungal infection (IFI) in immunosuppressed children and neonates. This multicenter observational study describes the inpatient prescribing practice of antifungal drugs for children and neonates and identifies factors associated with prescribing variability. A single-day point prevalence study of antimicrobial use in hospitalized neonates and children was performed between October and December 2012. The data were entered through a study-specific Web-based portal using a standardized data entry protocol.

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Section: Discussionmentioning

confidence: 99%

Systemic Antifungal Prescribing in Neonates and Children: Outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study

Lestner

Versporten

Doerholt

et al. 2015

Antimicrob Agents Chemother

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“…The potential role of transporters in renal clearance will also have to be investigated in further studies (35). The optimization of dosing for antimicrobial therapy should take into consideration developmental pharmacokinetics-pharmacodynamics, microbiology, and safety (36,37). The pharmacokinetic-pharmacodynamic parameter that correlates with the clinical and bacteriological efficacy of ␤-lactam antibiotics is the percentage of time that the serum free drug concentration exceeds the MIC for the pathogen (time above the MIC [T MIC ]) (12,38).…”

Section: Figmentioning

confidence: 99%

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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“…The approach takes into account drug-induced "adaptive resistance," which is reversible within days [reviewed in (4,10)]; it does not consider irreversible resistance caused, e.g., by bacterial mutations (11,12). It predicts standard intravenous injection dosing regimens may sometimes drive the average CFU number per patient to <1.…”

Section: Pk/pd Modelingmentioning

confidence: 99%

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

Radivoyevitch

Siranart

Hlatky

et al. 2015

AAPS J

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ABSTRACT. We consider dosing regimens designed to cure patients by eradicating colony forming units (CFU) such as bacteria. In the field of "population" pharmaco-kinetics/dynamics (PK/PD), interindividual variability (IIV) of patients is estimated using model parameter statistical distributions. We consider a more probabilistic approach to IIV called stochastic process theory, motivated by the fact that tumor treatment planning uses both approaches. Stochastic process PD can supply additional insights and suggest different dosing regimens due to its emphasis on the probability of complete CFU eradication and its predictions on "pure chance" fluctuations of CFU number per patient when treatment has reduced this integer to less than~100. To exemplify the contrast between stochastic process PD models and standard deterministic PD models, which track only average CFU number, we analyze, neglecting immune responses, neonatal intravenous gentamicin dosing regimens directed against Escherichia coli. Our stochastic calculations predict that the first dose is crucial for CFU eradication. For example, a single 6 mg/kg dose is predicted to have a higher eradication probability than four daily 4 mg/kg doses. We conclude: (1) neonatal gentamicin dosing regimens with larger first doses but smaller total doses deserve investigation; (2) in general, if standard PK/PD models predict average CFU number drops substantially below 100, the models should be modified to incorporate stochastic effects more accurately, and will then usually make more favorable, or less unfavorable, predictions for front boosting ("hit hard early"). Various caveats against over-interpreting the calculations are given.

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Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology

Cited by 33 publications

References 197 publications

Systemic Antifungal Prescribing in Neonates and Children: Outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study

Systemic Antifungal Prescribing in Neonates and Children: Outcomes from the Antibiotic Resistance and Prescribing in European Children (ARPEC) Study

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

Stochastic Process Pharmacodynamics: Dose Timing in Neonatal Gentamicin Therapy as an Example

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