Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients

Bukkems, Laura H.; Roger, Claire; Hodiamont, Caspar J.; Lefrant, Jean‐Yves; Juffermans, Nicole P.; Roberts, Jason A.; Hest, Reinier M. van

doi:10.1016/j.ijantimicag.2018.04.016

Cited by 12 publications

(7 citation statements)

References 21 publications

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“…One-and two-compartment models were both reported for gentamicin, 11,12,30 and our dataset was adequately described by the one-compartment model. The use of a one-compartment model for this dataset can also be visually evident from the gentamicin concentration-time profiles (Figure 1).…”

Section: Discussionmentioning

confidence: 82%

“…Using the final model, the efficacy and toxicity of gentamicin in CRRT patients under different gentamicin regimens and CRRT effluent doses were evaluated by the Monte Carlo simulation approach. A total of 15 treatment options were proposed based on the combinations of gentamicin regimens (3, 4, 5, 6, and 7 mg/kg q24h with an infusion period of 30 min) and CRRT effluent doses (30,40, and 50 mL/kg/h). For each simulation, 10,000 virtual critically ill patients were selected from the MIMIC-III database, 27 which is publicly available and comprises de-identified health-related data associated with over 40,000 patients who stayed in critical care units of the Beth Israel Deaconess Medical Center between 2001 and 2012.…”

Section: Simulation-based Treatment Optimizationmentioning

confidence: 99%

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Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Zhang

Xie

2022

DDDT

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Purpose: Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin. Methods: Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3-7 mg/kg q24h) and CRRT effluent doses (30-50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (C max /MIC > 10) and the ratio of area under the drug concentration-time curve/MIC over 24 h (AUC 0-24h /MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L). Results: A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC 0-24h /MIC >100 and risk of toxicity. Conclusion: A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.

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Section: Discussionmentioning

confidence: 82%

Section: Simulation-based Treatment Optimizationmentioning

confidence: 99%

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Zhang

Xie

2022

DDDT

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“…We aimed to review the clinical pharmacokinetics and consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria in various patient populations, focusing on new insights from the past decade. Several new PPK studies have focused on specific subpopulations including obese patients [46], critically ill patients [66,68,148], paediatric patients [90,92,106,149], neonates [112,[115][116][117][118]122], elderly patients [126] and patients on IHD [64,137], providing insights into the typical values of CL and V d in these patient groups, the variability of these parameters and possible explanations for this variability. But despite inclusion of covariates in many of these PPK models, unexplained IIV in CL and V d often remained high, especially in critically ill patients, resulting in wide ranges of C max , C min and AUC.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

et al. 2022

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Gentamicin is an aminoglycoside antibiotic with a small therapeutic window that is currently used primarily as part of shortterm empirical combination therapy. Gentamicin dosing schemes still need refinement, especially for subpopulations where pharmacokinetics can differ from pharmacokinetics in the general adult population: obese patients, critically ill patients, paediatric patients, neonates, elderly patients and patients on dialysis. This review summarizes the clinical pharmacokinetics of gentamicin in these patient populations and the consequences for optimal dosing of gentamicin for infections caused by Gram-negative bacteria, highlighting new insights from the last 10 years. In this period, several new population pharmacokinetic studies have focused on these subpopulations, providing insights into the typical values of the most relevant pharmacokinetic parameters, the variability of these parameters and possible explanations for this variability, although unexplained variability often remains high. Both dosing schemes and pharmacokinetic/pharmacodynamic (PK/PD) targets varied widely between these studies. A gentamicin starting dose of 7 mg/kg based on total body weight (or on adjusted body weight in obese patients) appears to be the optimal strategy for increasing the probability of target attainment (PTA) after the first administration for the most commonly used PK/PD targets in adults and children older than 1 month, including critically ill patients. However, evidence that increasing the PTA results in higher efficacy is lacking; no studies were identified that show a correlation between estimated or predicted PK/PD target attainment and clinical success. Although it is unclear if performing therapeutic drug monitoring (TDM) for optimization of the PTA is of clinical value, it is recommended in patients with highly variable pharmacokinetics, including patients from all subpopulations that are critically ill (such as elderly, children and neonates) and patients on intermittent haemodialysis. In addition, TDM for optimization of the dosing interval, targeting a trough concentration of at least < 2 mg/L but preferably < 0.5-1 mg/L, has proven to reduce nephrotoxicity and is therefore recommended in all patients receiving more than one dose of gentamicin. The usefulness of the daily area under the plasma concentration-time curve for predicting nephrotoxicity should be further investigated. Additionally, more research is needed on the optimal PK/PD targets for efficacy in the clinical situations in which gentamicin is currently used, that is, as monotherapy for urinary tract infections or as part of short-term combination therapy.

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“…This lack of external validation could be due to the difficulty of collecting data from enough patients with similar characteristics from another ICU to build a high-quality validation dataset. Furthermore, external validation in antimicrobials is known to often lead to inadequate bias and inaccuracy values [ 62 , 63 , 64 ], thus suggesting that a certain challenge still remains.…”

Section: Discussionmentioning

confidence: 99%

Aminoglycosides in the Intensive Care Unit: What Is New in Population PK Modeling?

et al. 2021

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Background: Although aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Objective: This review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in the ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Method: A literature search was conducted in the Medline/PubMed database, using the terms: ‘amikacin’, ’gentamicin’, ’tobramycin’, ‘pharmacokinetic(s)’, ’nonlinear mixed effect’, ’population’, ‘intensive care’, and ‘critically ill’. Results: Nineteen articles were retained where amikacin, gentamicin, and tobramycin pharmacokinetics were described in six, 11, and five models, respectively. A two-compartment model was used to describe amikacin and tobramycin pharmacokinetics, whereas a one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusions: This review showed models developed for amikacin, from 2015 until now, and for gentamicin and tobramycin from the past decades. Despite the growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients.

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Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients

Abstract: The model is valid for use in the AMC ICU population but not in the CHU Nîmes ICU population. This illustrates that caution is needed when using a population PK model in an external population.

Cited by 12 publications

References 21 publications

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Clinical Pharmacokinetics of Gentamicin in Various Patient Populations and Consequences for Optimal Dosing for Gram-Negative Infections: An Updated Review

Aminoglycosides in the Intensive Care Unit: What Is New in Population PK Modeling?

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