Extended-interval gentamicin: Population pharmacokinetics in pediatric critical illness

Lopez, Sara Arenas; Mulla, Hussain; Durward, Andrew; Tibby, Shane M.

doi:10.1097/pcc.0b013e3181b80693

Cited by 39 publications

(66 citation statements)

References 38 publications

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“…From the literature search, only three population pharmacokinetic models of gentamicin developed in pediatric populations were identified (Table 3) (16,17,21). These models, together with the final model from this study, were tested regarding their predictive performance with the external data set.…”

Section: Resultsmentioning

confidence: 99%

“…Few population pharmacokinetic models of gentamicin have been developed in children between 2 and 18 years of age (16)(17)(18), and to our knowledge, no models specifically characterizing pediatric oncology patients currently exist. Application of a relevant population model in a Bayesian forecasting program would likely improve the individualization of gentamicin dosing in pediatric oncology patients (15,19).…”

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confidence: 99%

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A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

Llanos-Paez

Staatz

Lawson

et al. 2017

Antimicrob Agents Chemother

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To ensure the safe and effective dosing of gentamicin in children, therapeutic drug monitoring (TDM) is recommended. TDM utilizing Bayesian forecasting software is recommended but is unavailable, as no population model that describes the pharmacokinetics of gentamicin in pediatric oncology patients exists. This study aimed to develop and externally evaluate a population pharmacokinetic model of gentamicin to support personalized dosing in pediatric oncology patients. A nonlinear mixed-effect population pharmacokinetic model was developed from retrospective data. Data were collected from 423 patients for model building and a further 52 patients for external evaluation. A two-compartment model with first-order elimination best described the gentamicin disposition. The final model included renal function (described by fat-free mass and postmenstrual age) and the serum creatinine concentration as covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow CL, 5.77 liters/h/70 kg; central volume of distribution, 21.6 liters/70 kg; peripheral volume of distribution, 13.8 liters/70 kg; and intercompartmental clearance, 0.62 liter/h/70 kg. External evaluation suggested that current models developed in other pediatric cohorts may not be suitable for use in pediatric oncology patients, as they showed a tendency to overpredict the observations in this population. The final model developed in this study displayed good predictive performance during external evaluation (root mean square error, 46.0%; mean relative prediction error, Ϫ3.40%) and may therefore be useful for the personalization of gentamicin dosing in this cohort. Further investigations should focus on evaluating the clinical application of this model. KEYWORDS pharmacokinetics, gentamicin, NONMEM, pediatrics, oncology, pharmacometrics, population pharmacokinetics F ebrile neutropenia induced by chemotherapy is a common complication in pediatric oncology patients. Neutropenic patients are more susceptible to the development of infections (1). Sepsis is the primary cause of mortality and morbidity in pediatric oncology patients with febrile neutropenia (2). The rate of mortality due to sepsis is 1.6-fold higher for oncology pediatric patients than it is for other pediatric patients (3). Aminoglycoside antibiotics, such as gentamicin, in combination with other broad-spectrum antibacterial agents play an important role in managing infectious complications in these individuals and are used as second-line therapies when treating Gram-negative bacterial infections and when resistance to first-line agents develops (4).Gentamicin has a narrow therapeutic window and displays large pharmacokinetic variability. High levels of and prolonged exposure to gentamicin has been associated with nephro-and ototoxicity (5, 6). Pediatric oncology patients often receive long

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

Llanos-Paez

Staatz

Lawson

et al. 2017

Antimicrob Agents Chemother

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“…We also searched the reference lists in identified papers. The authors of the publications that met the inclusion criteria (n ϭ 8) (11,15,21,22,(28)(29)(30)(31) were then invited to contribute their data.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

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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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“…With pharmacodynamics in mind, careful investigation of pharmacokinetic development is imperative to fully optimize antimicrobial dosing. With increasing bacterial MICs to aminoglycosides, conventional doses may not attain a desired peak concentration to optimize the peak:MIC ratio [21,23]. Given the short half-lives of β-lactam antimicrobials in children, traditional infusion times (those of 30 min or less) may have a lower probability of target attainment in infections due to bacteria with elevated MICs [13,14].…”

Section: Discussionmentioning

confidence: 99%

Optimized Antimicrobial Dosing Strategies: A Survey of Pediatric Hospitals

2014

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Abstract:Background Extended-interval aminoglycoside (EIAG) and extended-and continuous-infusion β-lactam (EIBL and CIBL) dosing strategies are increasingly used in adults, but pediatric literature is limited. ObjectiveThe objective of this study was to describe the use of EIAG, EIBL, and CIBL dosing in pediatric hospitals in the USA. Study Design, Setting, and ParticipantsA national survey of children's hospitals was conducted. A single practitioner from each target hospital was identified through the Children's Hospital Association. Practice-based survey questions identified whether hospitals utilize EIAG, EIBL, and CIBL dosing. Main Outcome MeasureThe main outcome measure was the percentage utilization of the dosing strategies, with secondary outcomes being the reasons for not using these dosing strategies. ResultsSeventy-seven of 215 identified practitioners (36 %) participated in the survey. EIAG, EIBL, and CIBL dosing were utilized in 63 %, 24 %, and 13 % of responding hospitals, respectively. The most common reasons for not using EIAG were concern regarding lack of efficacy data (56 %) and concern regarding the duration of the drug-free period (41 %). Respondents who did not utilize EIBL cited concern due to lack of pediatric EIBL efficacy data (54 %), the need for more intravenous access (54 %), intravenous medication compatibility issues (39 %), and the time during which the patient is attached to an intravenous infusion (31 %). ConclusionThis survey of children's hospitals indicates that EIAG is used in over 50 % of hospitals, but there is some lag in adoption of EIBL and CIBL dosing, both of which are used in fewer than 25 % of hospitals.Additional studies may provide much-needed evidence to increase the utilization of these strategies.2

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Extended-interval gentamicin: Population pharmacokinetics in pediatric critical illness

Abstract: A gentamicin dose of 8 mg/kg is highly likely to achieve peak concentrations >16 mg/L in critically ill children. A considerable proportion will require dose intervals >24 hrs; thus, therapeutic drug monitoring is essential.

Cited by 39 publications

References 38 publications

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

A Population Pharmacokinetic Model of Gentamicin in Pediatric Oncology Patients To Facilitate Personalized Dosing

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

Optimized Antimicrobial Dosing Strategies: A Survey of Pediatric Hospitals

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