Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data

Germovsek, Eva; Osborne, Leanne; Gunaratnam, F; Lounis, Shehrazed A; Busquets, F Bossacoma; Standing, Joseph F.; Sinha, Ajay

doi:10.1093/jac/dky525

Cited by 25 publications

(21 citation statements)

References 47 publications

(59 reference statements)

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“…The non-statistically significant effect of PMA and serum creatinine on clearance in the current study could be due to the small sample size and narrow variations in PMA and serum creatinine values. Nevertheless, our findings are consistent with those of Germovsek et al [18], who reported that serum creatinine had no significant effect on vancomycin clearance.…”

Section: Discussionsupporting

confidence: 93%

“…We could only measure trough concentrations of vancomycin, and no blood was drawn during the distribution phase, which could result in estimations of V d with low precision. We also reported low variations in clearance (4 vs. 32%), which was lower than that reported in the literature [18] and could have underestimated the variations in simulated AUC. However, we circumvented this problem by using a Bayesian approach (a priori information) to estimate the pharmacokinetic parameters.…”

Section: Discussioncontrasting

confidence: 77%

“…Additionally, prior information on vancomycin pharmacokinetics used in Bayesian estimations of pharmacokinetic parameters in our study was derived from the data that had both peak and trough concentrations. The number of neonates was also greater than in our study [18].…”

Section: Discussioncontrasting

confidence: 72%

“…Other studies involving paediatric populations reported similarly high variations in V d (43 and 77%) [24,25]. In contrast, some studies in neonatal populations reported low variations in vancomycin V d (32 and 29.4%) [9,18]. Studies [26][27][28] have shown sepsis to be associated with high values of V d due to the increase in capillary permeability that results in interstitial oedema.…”

Section: Discussionmentioning

confidence: 96%

“…We obtained prior information on vancomycin pharmacokinetic parameters in neonates for Bayesian estimation (maximum a posteriori estimation) of population pharmacokinetic parameters from the literature. This prior information was derived from 54 neonates who provided peak and trough vancomycin concentrations [18]. The estimation algorithm used was stochastic approximation expectation maximisation.…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates

et al. 2020

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Background The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA), varies between paediatric and adult patients. Objective The objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen. Methods This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration-time curve up to 24 h (AUC 0-24h) of ≥ 400 mg × h/L. Results In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3-58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC 0-24h of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h. Conclusion The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC 0-24h target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.

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Section: Discussionsupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 77%

Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 96%

Section: Pharmacokinetic Analysismentioning

confidence: 99%

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Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates

et al. 2020

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Using population pharmacokinetics to optimize initial vancomycin dosing guidelines for neonates to treat sepsis caused by coagulase‐negative staphylococcus

Chung

Seto

2023

Pharmacotherapy

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IntroductionVancomycin dosing tailored for newborns is challenging due to the significant influence of maturation and organ function on pharmacokinetics. Population pharmacokinetic (popPK) models can be used to improve target attainment in neonates.ObjectivesThe primary objective was to derive and evaluate a popPK model of intravenous vancomycin for neonates. Secondly, the predictive performance of this popPK model was compared with published popPK models.MethodsThis is a retrospective cohort study of neonates admitted to the neonatal intensive care unit receiving intravenous vancomycin. A popPK model was derived with 70% of the dataset using a nonlinear mixed effects modelling method. The predictive performance of the current popPK model was validated and compared with 22 published popPK models using the remaining 30% of the dataset. Monte Carlo simulations (MCS) were performed to derive optimal dosing regimens to treat neonatal sepsis caused by coagulase‐negative staphylococci (CoNS).ResultsAmong 655 vancomycin courses from 448 neonates, 78% of vancomycin trough concentrations were outside target range (10‐15 mg/L) for central nervous system infections and 43% were outside target range (5‐12 mg/L) for other infections using the institution's vancomycin dosing. A one‐compartment model best described the observed data with a mean clearance of 0.11±0.03 L/kg/h and volume of distribution (V) of 1.02±0.08 L/kg. Body weight, postmenstrual age (PMA), and serum creatinine (SCr) were significant covariates associated with clearance (p<0.001) and body weight was a significant covariate associated with V (p=0.009). Our study's popPK model has similar or better accuracy and precision than other published models. MCS‐derived vancomycin doses from the validated model achieved >90% target attainment for a steady state trough target range of 10‐15 mg/L in the majority of PMA and SCr categories (78%) to treat CoNS sepsis.ConclusionA vancomycin dosing guideline derived from a validated popPK model in neonates with CoNS sepsis is recommended to improve target attainment.

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External evaluation of neonatal vancomycin population pharmacokinetic models: Moving from first‐order equations to Bayesian‐guided therapeutic monitoring

Blouin,

Métras,

Gaudreault

et al. 2024

Pharmacotherapy

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IntroductionGuidelines for vancomycin therapeutic monitoring recommend using a Bayesian approach with a population pharmacokinetic model to estimate the 24 h area under the concentration‐time curve over first‐order equations. Thus, we performed an external evaluation of population pharmacokinetic models of vancomycin in neonates and compared Bayesian results with those observed in clinical practice via pharmacokinetic equations to improve therapeutic monitoring by proposing optimized initial dosing nomograms and assessing the feasibility of reduced blood sampling strategies using the most predictive models.MethodsModels were identified from the literature and evaluated via an external neonatal population. A priori predictive performance was first assessed by prediction‐based diagnostics, then by simulation‐based diagnostics and a posteriori analyses only if deemed satisfactory; model‐informed vancomycin exposure was also compared with reference first‐order pharmacokinetic equations. The best‐performing models were ultimately subjected to Monte Carlo simulations to develop new initial dosing nomograms offering the highest probability of achieving therapeutic target.ResultsA total of 28 population pharmacokinetic models were evaluated in the external dataset, which includes 72 neonates and 380 vancomycin concentrations. Eleven models had an adequate predictive performance with bias ≤ ± 15% and imprecision 30%, while the Bayesian approach yielded over 75% agreement with reference exposure values in most cases. Nonetheless, Capparelli et al. and Mehrotra et al. models performed the best overall, showing the lowest imprecisions of 16.8% and 16.9%, respectively; both models recommended higher dosage regimens than the theoretical nomogram currently applied to favor therapeutic target attainment.DiscussionWe externally evaluated numerous neonatal population pharmacokinetic models of vancomycin and used the most predictive ones to advocate new initial dosing nomograms. Clinical implementation of the Bayesian approach could reduce the time needed to reach therapeutic target and limit the number of blood samples in newborns compared with traditional pharmacokinetic equations.

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Development and external evaluation of a population pharmacokinetic model for continuous and intermittent administration of vancomycin in neonates and infants using prospectively collected data

Cited by 25 publications

References 47 publications

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates

Assessment of Vancomycin Pharmacokinetics and Dose Regimen Optimisation in Preterm Neonates

Using population pharmacokinetics to optimize initial vancomycin dosing guidelines for neonates to treat sepsis caused by coagulase‐negative staphylococcus

External evaluation of neonatal vancomycin population pharmacokinetic models: Moving from first‐order equations to Bayesian‐guided therapeutic monitoring

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