Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia

Sampson, Mario R.; Frymoyer, Adam; Rattray, Benjamin; Cotten, C. Michael; Smith, Paul; Capparelli, Edmund V.; Bonifacio, Sonia L.; Cohen‐Wolkowiez, Michael

doi:10.1097/ftd.0000000000000056

Cited by 26 publications

(26 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the CL values between the two investigations were notably different with an estimate of 1 ml/minute/kg versus 2.2 ml/minute/kg, respectively . Both of the CL estimates are higher than previously reported in neonates with HIE receiving CH, in normothermic neonates with HIE, and normothermic neonates without HIE with CL ranges reported from 0.4–0.8 ml/minute/kg . Interestingly, the two prospective pharmacokinetic investigations found CH to increase the CL of gentamicin.…”

Section: Discussioncontrasting

confidence: 59%

“…Given the potential adverse effects of gentamicin on auditory and renal function, additional data describing the pharmacokinetics and resulting pharmacodynamics in the setting of CH were undertaken. Most of the available literature to date retrospectively evaluated gentamicin peak and/or trough serum concentrations . One study reported no difference in gentamicin trough concentrations between cooled and normothermic neonates with HIE .…”

Section: Discussionmentioning

confidence: 99%

“…One study reported no difference in gentamicin trough concentrations between cooled and normothermic neonates with HIE . A reduced gentamicin CL was observed when comparing neonates with HIE receiving CH with either historical normothermic controls or previously reported values in normothermic non‐HIE neonates . The weaknesses of these previous investigations are their retrospective design and their reliance on only peak and/or trough concentrations to determine the pharmacokinetics of gentamicin rather than using a more robust sampling schedule for obtaining additional gentamicin serum concentrations to aid in determining the pharmacokinetic profile.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic‐Ischemic Encephalopathy Receiving Controlled Hypothermia

et al. 2018

View full text Add to dashboard Cite

Objective Identify population pharmacokinetics and pharmacodynamic target attainment of gentamicin in neonates with hypoxic‐ischemic encephalopathy (HIE) undergoing controlled hypothermia (CH). Design Prospective open‐label pharmacokinetic study. Gentamicin concentrations were modeled and dosing regimens simulated for a 5000‐patient neonatal population with HIE receiving CH using PMetrics, a nonparametric, pharmacometric modeling, and simulation package for R. Setting A 189‐bed children's tertiary care teaching hospital. Results Twelve patients, 5 (42%) females and 7 (58%) males, met inclusion criteria with a median gestation age of 39.9 weeks (interquartile range [IQR] 38.5–40.2 wks) and a median birthweight (BW) of 3.3 kg (IQR 3.1–3.7 kg). Gentamicin concentrations were best described by a two‐compartment model with first‐order elimination with BW as a covariate on volume of distribution (Vd). The mean total body population clearance (CL) was 2.2 ± 0.7 ml/minute/kg, and the volume of the central compartment was 0.44 ± 0.06 L/kg. The R2, bias, and precision for the observed versus population predicted model were 0.917, 1.15, and 10.9 μg/ml; the R2, bias, and precision for the observed versus individual predicted model were 0.982, −0.132, and 0.932 μg/ml, respectively. The calculated mean population estimate for the total Vd was 0.96 ± 0.4 L/kg. The dosing regimen that most consistently produced a maximum concentration (Cmax) in the range of 10–12 mg/L with a minimum concentration (Cmin) level less than 2 mg/L was 5 mg/kg/dose given every 36 hours. Conclusion These data suggest the population pharmacokinetics of gentamicin in neonates with HIE receiving CH have an increase in gentamicin CL and are different from previous reports in neonates with HIE not receiving CH and/or neonates without HIE. This analysis suggests a dosing regimen of 5 mg/kg/dose every 36 hours results in a gentamicin Cmax within the range of 10–12 mg/L with a Cmin lower than 2 mg/L, which is appropriate for treating susceptible gram‐negative organisms with minimum inhibitory concentrations of 1 mg/L or lower.

show abstract

Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic‐Ischemic Encephalopathy Receiving Controlled Hypothermia

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Measured creatinine Cl that involves 24‐hour urine collection would yield more accurate results, but the method is not applicable in routine clinical practice in paediatric intensive care units. Special attention should be given to newborns whose serum creatinine concentrations also reflect the maternal renal function and maternal creatinine because serum creatinine is transported across the placenta in both directions . In newborns and infants, the renal function changes due to maturation, but older paediatric patients submitted to intensive care units can also have considerably reduced renal function.…”

Section: Discussionmentioning

confidence: 99%

A review of population pharmacokinetic models of gentamicin in paediatric patients

2019

View full text Add to dashboard Cite

What is known and objectives Gentamicin is often used for the treatment of Gram‐negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. Methods The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. Results and discussion In most of the studies, one‐ or two‐compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. What is new and conclusion Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat‐free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.

show abstract

“…The bias and precision of clearance prediction were assessed through calculation of average fold error (AFE) and absolute average fold error (AAFE) using the following:

A F E = 10^{\frac{1}{N} Σ \log (\frac{C L_{p r e d i c t e d}}{C L_{o b s e r v e d}})}

A A F E = 10^{\frac{1}{N} Σ (\log \frac{C L_{p r e d i c t e d}}{C L_{o b s e r v e d}})}

where N denotes the number of neonates in the neonatal trial. An AFE greater than 1 suggests a bias toward overprediction, and an AFE less than 1 suggests a bias toward underprediction.…”

Section: Methodsmentioning

confidence: 99%

Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling

Wang

Edginton

Avant

et al. 2015

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates.

show abstract

Predictive Performance of a Gentamicin Population Pharmacokinetic Model in Neonates Receiving Full-Body Hypothermia

Cited by 26 publications

References 20 publications

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic‐Ischemic Encephalopathy Receiving Controlled Hypothermia

Population Pharmacokinetics of Gentamicin in Neonates with Hypoxemic‐Ischemic Encephalopathy Receiving Controlled Hypothermia

A review of population pharmacokinetic models of gentamicin in paediatric patients

Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling

Contact Info

Product

Resources

About