Clinical applications of population pharmacokinetic models of antibiotics: Challenges and perspectives

Velde, Femke de; Mouton, Johan W.; Winter, Brenda C M de; Gelder, Teun van; Koch, Birgit C. P.

doi:10.1016/j.phrs.2018.07.005

Cited by 107 publications

(103 citation statements)

References 62 publications

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“…Second, in interpreting the simulations, we chose a target PTA of 90% for selection of the best dose regimen, as advocated by the EMA . However, certain situations may call for a higher target PTA and therefore a higher dosage, for example in serious life‐threatening infections . In addition, the target for PTA (AUC 24 > 400 mg h L −1 ), has only been established for S. aureus infections.…”

Section: Discussionmentioning

confidence: 99%

“…39 However, certain situations may call for a higher target PTA and therefore a higher dosage, for example in serious lifethreatening infections. 39,40 In addition, the target for PTA (AUC 24 > 400 mg h L −1 ), has only been established for S. aureus infections. We still remain fairly ignorant as to the appropriate targets for other infections where vancomycin is indicated.…”

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Smit

Wasmann

Goulooze

et al. 2020

Brit J Clinical Pharma

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Aims For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400–700 mg h L−1). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. Methods Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0–234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg−1, maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11–13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60–230 kg) were performed using NONMEM. Results In a 3‐compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg−1 day−1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L−1) in individuals up to 200 kg, with corresponding trough concentrations of 5.7–14.6 mg L−1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1. Conclusion In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg−1 day−1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7–14.6 mg L−1 correspond to the target exposure in obese individuals.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Smit

Wasmann

Goulooze

et al. 2020

Brit J Clinical Pharma

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“…Gentamicin has been widely used for decades in the treatment of Gram‐negative bacterial infection and thoroughly examined in pediatric patients . However, high variability and unpredictability of gentamicin's pharmacokinetics (PK) in pediatric populations still exist, which reinforce the value of individualized dosing.…”

mentioning

confidence: 99%

“…Gentamicin has been widely used for decades in the treatment of Gram-negative bacterial infection and thoroughly examined in pediatric patients. 1,2 However, high variability and unpredictability of gentamicin's pharmacokinetics (PK) in pediatric populations still exist, which reinforce the value of individualized dosing. Currently, there are many forms of translating therapeutic drug monitoring (TDM) data into individualized dose recommendations, the newest of which is via Bayesian inference, which offers unique advantages over the earlier forms of dose adjustment nomograms and linear regression analyses.…”

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confidence: 99%

Population Pharmacokinetic Modeling of Gentamicin in Pediatrics

Wang

Sherwin

Gobburu

et al. 2019

The Journal of Clinical Pharma

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The primary objective of this work was to characterize the pharmacokinetics (PK) of gentamicin across the whole pediatric age spectrum from premature neonates to young adults with a single model by identifying significant clinical predictors. A nonlinear mixed‐effect population PK model was developed with retrospective therapeutic drug‐monitoring data. A total of 6459 drug concentration measurements from 3370 hospitalized patients were collected for model building (n = 2357) and evaluation (n = 1013). In agreement with previously reported models, a 2‐compartment model with first‐order elimination best described the drug PK. Patient‐specific factors significantly impacting gentamicin clearance included fat‐free mass, postmenstrual age, and serum creatinine (SCr). Based on our model, the deviation of the individual SCr from the age‐dependent expected mean SCr value (SCrM) can result in a 40% lower clearance in a patient with renal impairment than that in a patient with normal kidney function, with SCrM:SCr ratios between 0.16 and 3.2 in this study. Consistent with the known age‐dependent changes of the proportion of extracellular water in body weight, the inclusion of the impact of extracellular water maturation on the central volume of distribution was found to improve the model fitting significantly. In comparison with other published models, model evaluation suggested the developed model was the least biased and physiologically most representative. These results will be used to inform individualized initial dosing strategies and serve as a prior PK model for Bayesian updating and forecasting as individual clinical observations become available.

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“…TDM of amikacin aims to minimize risks of toxicity and maximize therapeutic efficacy . Since only a limited number of blood concentrations can be ethically obtained from hospitalized pediatric patients, the PopPK approach using nonlinear mixed‐effect modeling to obtain PK parameters is an ideal tool for PK analysis in this population …”

Section: Discussionmentioning

confidence: 92%

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

Guido

Pérez

Halac

et al. 2019

Pediatric Pulmonology

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Introduction Amikacin is commonly used in patients with pediatric cystic fibrosis (CF) for the treatment of pulmonary exacerbations. Amikacin efficacy is related to maximum plasma concentration/minimum inhibitory concentration (Cmax/MIC) ratio >8. Pharmacokinetic data in patients with pediatric CF are scarce. The aim of this study was to develop a population pharmacokinetic (PopPK) model describing amikacin disposition in patients with pediatric CF. Methods CF patients under 18 years of age with pulmonary exacerbation who received amikacin were enrolled. Patients received different amikacin regimens (30 mg−1 kg−1 day−1 every 8, 12, or 24 hours) depending on the patient's status and hospital protocols. Amikacin serum levels were obtained for therapeutic drug monitoring. PopPK model was developed using MONOLIX Suite‐2018R1 (Lixoft). Results A total of 39 patients (114 amikacin concentrations) were included in this study. Population estimates for the elimination rate constant (k) and the volume of distribution (V) were 0.541 hours−1 and 0.451 L/kg, respectively. Between‐subject and between‐occasion variability were 53% and 16.5% for k and 31% and 22% for V, respectively. Bodyweight was a significant covariate associated with V. Based on simulations, almost 70% of the patients receiving 30 mg−1 kg−1 day−1 every 24 hours would achieve a Cmax/MIC ratio >8 which is an appropriate therapeutic goal while no patient in the other two groups (Q8 and Q12) would achieve that objective. Conclusions The regimen of 30 mg−1 kg−1 day−1 every 24 hours more adequately fulfilled the therapeutic target for amikacin. Although all our patients had good clinical results and a good adverse‐events profile, further studies are necessary to redefine the optimal treatment strategy.

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Clinical applications of population pharmacokinetic models of antibiotics: Challenges and perspectives

Cited by 107 publications

References 62 publications

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Population pharmacokinetics of vancomycin in obesity: Finding the optimal dose for (morbidly) obese individuals

Population Pharmacokinetic Modeling of Gentamicin in Pediatrics

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

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