Population pharmacokinetics of gentamicin in premature newborns

García, Benito; Barcia, Emilia; Pérez, F.; Molina, Irene T

doi:10.1093/jac/dkl244

Cited by 46 publications

(50 citation statements)

References 23 publications

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“…BW also increases significantly during the first year of life; therefore, the introduction of such a covariate in the population pharmacokinetic analysis allows for a comparison of V with that of other populations. The mean value obtained for this parameter is in accordance with that of other studies, being lower than that reported for adult populations (0.28 liters/kg) and higher than that given for newborns (0.48 liters/kg) (27,28).…”

Section: Discussionsupporting

confidence: 91%

“…This population of infants exhibits different characteristics than those of newborns or adults (13,27,28). In the current study, the population pharmacokinetic parameters of gentamicin were retrospectively estimated by NONMEM 7.2 in a total population of 263 infants who were admitted to the Hospital Universitario Severo Ochoa (Leganés, Spain) between the years 1990 and 2011 and who received gentamicin as part of their treatment.…”

Section: Discussionmentioning

confidence: 99%

“…However, the two-compartment open model showed improved goodness of fit to represent the disposition of gentamicin in the population studied. Previous reports have also proposed the use of the two-compartment model to describe the pharmacokinetic behavior of gentamicin in different populations of infants (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…Gentamicin CL and V are different in infants compared to those in adults, showing wide interindividual variability. This difference can be attributed to several factors that contribute to the modification of the distribution of gentamicin, such as protein binding, blood flow to tissues, membrane permeability, and drug affinity for different tissues (27)(28)(29). The fact that gentamicin is a polar compound with low plasma protein binding (Ͻ30%) makes its V directly related to extracellular body fluid (5).…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

Medellín‐Garibay

Rueda-Naharro

Peña-Cabia

et al. 2015

Antimicrob Agents Chemother

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The aim of this study was to characterize and validate the population pharmacokinetics of gentamicin in infants and to determine the influences of clinically relevant covariates to explain the inter-and intraindividual variabilities associated with this drug. Infants receiving intravenous gentamicin and with routine therapeutic drug monitoring were consecutively enrolled in the study. Plasma concentration and time data were retrospectively collected from 208 infants (1 to 24 months old) of the Hospital Universitario Severo Ochoa (Spain), of whom 44% were males (mean age [؎ standard deviation], 5.8 ؎ 4.8 months; mean body weight, 6.4 ؎ 2.2 kg). Data analysis was performed with NONMEM 7.2. One-and two-compartment open models were analyzed to estimate the gentamicin population parameters and the influences of several covariates. External validation was carried out in another population of 55 infants. The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics, with total body weight being the covariate that mainly influences central volume (V c ) and clearance (CL); this parameter was also related to creatinine clearance. Both parameters are age related and different from those reported for neonatal populations. On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 mg/kg of body weight every 24 h is proposed for intravenous gentamicin, followed by therapeutic drug monitoring in order to avoid toxicity and ensure efficacy with minimal blood sampling. Gentamicin pharmacokinetics and disposition were accurately characterized in this pediatric population (infants), with the parameters obtained being different from those reported for neonates and children. These differences should be considered in the dosing and therapeutic monitoring of this antibiotic.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics of Gentamicin and Dosing Optimization for Infants

Medellín‐Garibay

Rueda-Naharro

Peña-Cabia

et al. 2015

Antimicrob Agents Chemother

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“…Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period.…”

mentioning

confidence: 99%

Development and Evaluation of a Gentamicin Pharmacokinetic Model That Facilitates Opportunistic Gentamicin Therapeutic Drug Monitoring in Neonates and Infants

Germovsek

Kent

Metsvaht

et al. 2016

Antimicrob Agents Chemother

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T he aminoglycoside antibiotic gentamicin is the most commonly used antimicrobial in neonatal units (1, 2) and is effective against Gram-negative bacteria. Gentamicin use is limited by its narrow therapeutic index and risk of toxicity, specifically, nephro-and ototoxicity (3). It is not metabolized in the liver (4) and is almost entirely eliminated by the kidneys; clearance therefore depends on renal function. During the first 2 weeks of life, renal and intrarenal blood flow increase rapidly, causing a steep rise in the glomerular filtration rate (GFR) (5, 6).Therapeutic drug monitoring (TDM) is required to ensure maximal efficacy and, in particular, minimal toxicity, particularly in the neonatal population, where the variability in pharmacokinetic (PK) parameters is large. Dose individualization approaches focus on toxicity (7, 8) and include single-level methods and nomograms (9, 10), area under the curve (AUC) methods (11), and Bayesian methods (12). The use of nomograms is limited as they cannot readily incorporate covariates affecting PK parameters. AUC methods use a simplified 1-compartment PK model and require at least two gentamicin measurements, which is not appropriate in neonates with limited blood volumes. These drawbacks make Bayesian approaches the most attractive for newborn infants.Deriving a Bayesian prior for TDM requires a nonlinear mixed-effect PK model, and several such studies of neonatal gentamicin were previously published (13-24). However, those studies were limited by their heterogeneity and use of sparse data (often identifying only a 1-compartment model, whereas gentamicin follows multicompartment kinetics [25,26]) and failed to account for age-related differences in creatinine levels during the immediate newborn period. Although gentamicin is not a new drug, its dosing and monitoring are still current issues as identified in the United Kingdom National Patient Safety alert (http://www.nrls .npsa.nhs.uk/alerts/?entryid45ϭ66271) and in a recent publication by Valitalo et al. (27), who used simulations to define dosing guidelines.We aimed to investigate whether opportunistic sampling can predict trough gentamicin concentrations so that standard TDM can be performed using a blood sample taken for other purposes Citation Germovsek E, Kent A, Metsvaht T, Lutsar I, Klein N, Turner MA, Sharland M, Nielsen EI, Heath PT, Standing JF, the neoGent Collaboration. 2016. Development and evaluation of a gentamicin pharmacokinetic model that facilitates opportunistic gentamicin therapeutic drug monitoring in neonates and infants.

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