Population Pharmacokinetics Of Vancomycin Research Articles

Pharmacokinetics of Vancomycin in Healthy Korean Volunteers and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients with Normal Renal Function.

Background/Objectives: To date, population pharmacokinetic (PK) studies of vancomycin on healthy Korean adults have not been conducted. This study aimed to investigate the PK properties of vancomycin in healthy volunteers and to identify optimal dosing regimens based on the area under the concentration-time curve (AUC) in adult patients with normal renal function. Methods: We conducted a prospective clinical study, analysing PK samples from 12 healthy participants using noncompartmental analysis and non-linear mixed-effects modelling. The population PK parameters derived were employed in Monte Carlo simulations to evaluate the adequacy of the current dosing regimen and to formulate dosing recommendations. Results: The PK profiles were optimally described by a two-compartment model, with body weight and age as significant covariates affecting total clearance. The simulations indicated that to achieve a therapeutic target-defined as an AUC at steady-state over 24 h of 400-600 mg·h/L-daily doses ranging from 60 to 70 mg/kg are necessary in adults with normal renal function. Conclusions: This study underscores the need to actively adjust dosage and administration based on a vancomycin PK model that adequately reflects the demographic characteristics of patients to meet both safety and efficacy standards.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Therapeutic drug monitoring data from initial vancomycin therapy (first 3days of treatment) in adult obese (BMI ≥ 30kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

Population pharmacokinetics of vancomycin in term neonates with perinatal asphyxia treated with therapeutic hypothermia.

Little is known about the population pharmacokinetics (PPK) of vancomycin in neonates with perinatal asphyxia treated with therapeutic hypothermia (TH). We aimed to describe the PPK of vancomycin and propose an initial dosing regimen for the first 48 h of treatment with pharmacokinetic/pharmacodynamic target attainment. Neonates with perinatal asphyxia treated with TH were included from birth until Day 6 in a multicentre prospective cohort study. A vancomycin PPK model was constructed using nonlinear mixed-effects modelling. The model was used to evaluate published dosing guidelines with regard to pharmacokinetic/pharmacodynamic target attainment. The area under the curve/minimal inhibitory concentration ratio of 400-600 mg*h/L was used as target range. Sixteen patients received vancomycin (median gestational age: 41 [range: 38-42] weeks, postnatal age: 4.4 [2.5-5.5] days, birth weight: 3.5 [2.3-4.7] kg), and 112 vancomycin plasma concentrations were available. Most samples (79%) were collected during the rewarming and normothermic phase, as vancomycin was rarely initiated during the hypothermic phase due to its nonempirical use. An allometrically scaled 1-compartment model showed the best fit. Vancomycin clearance was 0.17 L/h, lower than literature values for term neonates of 3.5kg without perinatal asphyxia (range: 0.20-0.32 L/h). Volume of distribution was similar. Published dosing regimens led to overexposure within 24 h of treatment. A loading dose of 10mg/kg followed by 24 mg/kg/day in 4 doses resulted in target attainment. Results of this study suggest that vancomycin clearance is reduced in term neonates with perinatal asphyxia treated with TH. Lower dosing regimens should be considered followed by model-informed precision dosing.

Population pharmacokinetics of vancomycin in hemodialysis patients

Population pharmacokinetics of vancomycin in hemodialysis patients

Population pharmacokinetics of vancomycin in patients with diabetic foot infection: a comparison of five models.

This study aimed to compare individual pharmacokinetic (PK) parameters of vancomycin with predicted values from five population PK models in patients with diabetic foot infections (DFIs). Patients with a diagnosis of DFI and an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min were included in the study. Individual PK data was carried on by collecting three vancomycin serum concentrations in a steady-state condition. Five published population-based nomograms were assumed to predict PK parameters. Optimal vancomycin exposure was considered as a trough level of 15-20mg/L or the area under the curve over 24h/minimum inhibitory concentration (AUC24/MIC) ≥ 400. A total of 48 samples from 16 patients were analyzed. There was a statistically significant difference between the volume of distribution (Vd) obtained from population methods and the individual estimations (P ≤ 0.001 in Ambrose and Burton, P = 0.010 and 0.006 in Bauer and Burton revised models, respectively). AUC/MIC ≥ 400 was achieved in 68.7% of patients while 50% had a trough level of less than 15mg/L. Vancomycin PK parameters, particularly individualized Vd, may not be predictable by population nomograms in patients with DFI and stable renal function. Moreover, the weak correlation between AUC24 values and trough concentrations underlines the starting practice of vancomycin AUC24-based monitoring and dosing in the clinical setting.

Vancomycin population pharmacokinetics analysis in Chinese paediatric patients with varying degrees of renal function and ages: development of new practical dosing recommendations.

To describe the pharmacokinetics of vancomycin in a large Chinese paediatric cohort with varying degrees of renal function and ages and to develop practical dosing guidelines. We conducted a retrospective population pharmacokinetic study using data from paediatric patients who received vancomycin between June 2013 and June 2022. A non-linear mixed-effect modelling approach with a one-compartment model structure was applied. Monte Carlo simulations were used to stimulate an optimal dosage regimen to achieve the target of AUC24/MIC between 400 and 650. We analysed a total of 673 paediatric patients and 1547 vancomycin serum concentrations. Covariate analysis revealed that physiological maturation, renal function, albumin and cardiothoracic surgery (CTS) significantly affected vancomycin pharmacokinetics. The typical clearance and volume of distribution, standardized to 70 kg, were 7.75 L/h (2.3% relative standard error, RSE) and 36.2 L (1.7% RSE), respectively. Based on the model, we proposed an optimal dosing regimen that considers the patient's age and estimate glomerular filtration rate (eGFR) to achieve a target AUC24/MIC for CTS and non-CTS patients. We also found that a loading dose of 20 mg/kg can help patients with an eGFR of <60 mL/min/1.73 m2 achieve the target AUC on the first day of treatment. We established vancomycin pharmacokinetic parameters in Chinese paediatric patients and proposed a dosing guideline integrating eGFR, age and CTS status, potentially improving clinical outcomes and reducing nephrotoxicity risk.

External validation of population pharmacokinetic models of vancomycin in postoperative neurosurgical patients.

Vancomycin is commonly used in the prevention and treatment of intracranial infections in postoperative neurosurgical patients with narrow therapeutic window and large pharmacokinetic variations. Several population pharmacokinetic (PPK) models of vancomycin have been established for neurosurgical patients. But comprehensive external evaluation has not been performed for almost all models. The objective of this study was to evaluate the predictive ability of published vancomycin PPK models in adult postoperative neurosurgical patients using an independent dataset. PubMed, Embase and China National Knowledge Internet databases were searched to identify published vancomycin PPK models in adult postoperative neurosurgical patients. Prediction-based and simulation-based diagnostics were used to evaluate model predictability. Bayesian forecasting was used to assess the influence of prior concentration on model prediction performance. A total of 763 vancomycin plasma concentrations from 493 postoperative neurosurgical patients were included in the external dataset. Eight population pharmacokinetic models of vancomycin in postoperative neurosurgical patients were included and evaluated. The model by Zhang et al. exhibited the best predictive performance in prediction-based diagnostics and prediction-corrected visual predictive checks, followed by the model by Shen et al. The predictive performance of other models was not satisfactory. The normalized predictive distribution error test shows that none of the models is suitable to describe our data. The predictive performance of vancomycin models was obviously improved by maximum a posteriori Bayesian forecasting. The published PPK models for adult postoperative neurosurgical patients show extensive variation in predictive performance in our patients. Although it is challenging to recommend initial doses of vancomycin from these predictive models, the combination of model-based prediction and therapeutic drug monitoring can be used for dose optimization.

Population pharmacokinetics of vancomycin in very low birth weight neonates.

Vancomycin dosing in very low birth weight (VLBW) neonates is challenging. Compared with the general neonatal population, VLBW neonates are less likely to achieve the vancomycin therapeutic targets. Current dosing recommendations are based on studies of the general neonatal population, as only a very limited number of studies have evaluated vancomycin pharmacokinetics in VLBW neonates. The main aim of this study was to develop a vancomycin population pharmacokinetic model to optimize vancomycin dosing in VLBW neonates. This multicenter study was conducted at six major hospitals in Saudi Arabia. The study included VLBW neonates who received vancomycin and had at least one vancomycin serum trough concentration measurement at a steady state. We developed a pharmacokinetic model and performed Monte Carlo simulations to develop an optimized dosing regimen for VLBW infants. We evaluated two different targets: AUC0-24 of 400-600 or 400-800 µg. h/mL. We also estimated the probability of trough concentrations >15 and 20 µg/mL. In total, we included 236 neonates, 162 in the training dataset, and 74 in the validation dataset. A one-compartment model was used, and the distribution volume was significantly associated only with weight, whereas clearance was significantly associated with weight, postmenstrual age (PMA), and serum creatinine (Scr). We developed dosing regimens for VLBW neonates, considering the probability of achieving vancomycin therapeutic targets, as well as different toxicity thresholds. The dosing regimens were classified according to PMA and Scr. These dosing regimens can be used to optimize the initial dose of vancomycin in VLBW neonates.

Population Pharmacokinetics of Vancomycin in Patients Receiving Hemodialysis in a Malian and a French Center and Simulation of the Optimal Loading Dose.

Vancomycin dosing remains challenging in patients receiving intermittent hemodialysis, especially in developing countries, where access to therapeutic drug monitoring and model-based dose adjustment services is limited. The objectives of this study were to describe vancomycin population PK in patients receiving hemodialysis in a Malian and French center and examine the optimal loading dose of vancomycin in this setting. Population pharmacokinetic analysis was conducted using Pmetrics in 31 Malian and 27 French hemodialysis patients, having a total of 309 vancomycin plasma concentrations. Structural and covariate analyses were based on goodness-of-fit criteria. The final model was used to perform simulations of the vancomycin loading dose, targeting a daily area under the concentration-time curve (AUC) of 400-600 mg.h/L or trough concentration of 15-20 mg/L at 48 hours. After 48 hours of therapy, 68% of Malian and 63% of French patients exhibited a daily AUC of <400. The final model was a 2-compartment model, with hemodialysis influencing vancomycin elimination and age influencing the vancomycin volume distribution. Younger Malian patients exhibited a lower distribution volume than French patients. Dosing simulation suggested that loading doses of 1500, 2000, and 2500 mg would be required to minimize underexposure in patients aged 30, 50, and 70 years, respectively. In this study, a low AUC was frequently observed in hemodialysis patients in Mali and France after a standard vancomycin loading dose. A larger dose is necessary to achieve the currently recommended AUC target. However, the proposed dosing algorithm requires further clinical evaluation.

Scoping review on population pharmacokinetics of vancomycin in non-critically ill

Background: Vancomycin is an effective first-line therapy in MRSA infection, however, achieving an appropriate serum concentration is challenging. Population pharmacokinetics can assist the clinician in the selection of better regimen dosing and improve effectiveness and safety outcomes. Methods: This scoping review aims to outline the evidence in population pharmacokinetic models in non-critical adults hospitalized from 1980 to 2021 and describe the principal software and covariables used in this. A total of 209 papers were fully screened. Finally, we included 17 articles conducted in different locations around the world. Results: This review identified 13 retrospective articles and 4 prospective, 5 describing the use in a general population with gram-positive bacterial infection, 11 evaluated special populations (older, obese, and cancer patients), and 1 mixed population. The main parameters in the models were renal clearance and volume of distribution. The principal covariables that affected the models were creatinine clearance and weight. All studies use internal validation methods, and three of them used an external validation group. This scoping review highlights the principal information of different population pharmacokinetic models and the heterogeneity in the parameters and methods of evaluation. Conclusions: These methods can be used to guide the dosing regimen in different subpopulations. However, it is imperative to define the best fit in every population and conduct an experiment due to the high variability in the present studies.

Scoping review on Population pharmacokinetics of vancomycin in non-critically ill

Scoping review on Population pharmacokinetics of vancomycin in non-critically ill

Scoping review on Population pharmacokinetics of vancomycin in hospitalized adults

Scoping review on Population pharmacokinetics of vancomycin in hospitalized adults

Scoping review on Population pharmacokinetics of vancomycin in hospitalized adults

Scoping review on Population pharmacokinetics of vancomycin in hospitalized adults

Population pharmacokinetic model of vancomycin in postoperative neurosurgical patients.

Objective: Vancomycin is commonly used in postoperative neurosurgical patients for empirical anti-infective treatment due to the low success rate of bacterial culture in cerebrospinal fluid (about 20%) and the high mortality of intracranial infection. At conventional doses, the rate of target achievement for vancomycin trough concentration is low and the pharmacokinetics of vancomycin varies greatly in these patients, which often leads to treatment failure. The objective of this study was to establish a population pharmacokinetic (PPK) model of vancomycin in postoperative neurosurgical patients for precision medicine. Method: A total of 895 vancomycin plasma concentrations from 560 patients (497 postoperative neurosurgical patients) were retrospectively collected. The model was analyzed by nonlinear mixed effects modeling method. One-compartment model and mixed residual model was employed. The influence of covariates on model parameters was tested by forward addition and backward elimination. Goodness-of-fit, bootstrap and visual predictive check were used for model evaluation. Monte Carlo simulations were employed for dosing strategies with AUC24 targets 400–600. Result: Estimated glomerular filtration rate (eGFR), body weight (BW) and mannitol had significant influence on vancomycin clearance (CL). , for female, a = 0.7, Scr 0.7 mg/dl, b = −0.329, Scr 0.7 mg/dl, b = −1.209; for male, a = 0.9, Scr 0.9 mg/dl, b = −0.411, Scr 0.9 mg/dl, b = −1.210. Vancomycin clearance was accelerated when co-medicated with mannitol and increased with eGFR and BW. In the final model, the population typical value is 7.98 L/h for CL and 60.2 L for apparent distribution volume, , where A = 0.13 when co-medicated with mannitol, otherwise A = 0. The model is stable and effective, with good predictability. Conclusion: In postoperative neurosurgical patients, a higher dose of vancomycin may be required due to the augmented renal function and the commonly used mannitol, especially in those with high body weight. Our vancomycin PPK model could be used for individualized treatment in postoperative neurosurgical patients.

Population Pharmacokinetics of Vancomycin in Pregnant Women.

Objective: Vancomycin is a glycopeptide antibacterial indicated for serious gram-positive infections. Pharmacokinetics (PK) of vancomycin have not been described in pregnant women. This study aims to characterize the PK disposition of vancomycin in pregnant women based on data acquired from a database of routine hospital care for therapeutic drug monitoring to better inform dosing decisions. Methods: In this study, plasma drug concentration data from 34 pregnant hospitalized women who were administered intravenous vancomycin was analyzed. A population pharmacokinetic (PPK) model was developed using non-linear mixed effects modeling. Model selection was based on statistical criterion, graphical analysis, and physiologic relevance. Using the final model AUC0-24 (PK efficacy index of vancomycin) was compared with non-pregnant population. Results: Vancomycin PK in pregnant women were best described by a two-compartment model with first-order elimination and the following parameters: clearance (inter individual variability) of 7.64 L/hr (32%), central volume of 67.35 L, inter-compartmental clearance of 9.06 L/h, and peripheral volume of 37.5 L in a typical patient with 175 ml/min creatinine clearance (CRCL) and 45 kg fat-free mass (FFM). The calculated geometric mean of AUC0-24 for the pregnant population was 223 ug.h/ ml and 226 ug.h/ ml for the non-pregnant population. Conclusion: Our analysis suggests that vancomycin PK in pregnant women is consistent with non-pregnant adults and the dosing regimens used for non-pregnant patients may also be applicable to pregnant patients.

External validation of vancomycin population pharmacokinetic models in ten cohorts of infected Chinese patients

Appropriate dosage of vancomycin is critical for safety and efficacy in treating infectious diseases. Various population pharmacokinetic (PPK) models have been established. To lay a foundation for the clinical application, it is important to perform external validation of the published model. The aim of this study was to find the most suitable vancomycin PPK model for treatment of infection in China amongst all studied models developed for adults. A systematic literature search of published population vancomycin pharmacokinetic analyses was performed using the PubMed database. The identified models were evaluated in ten independent cohorts from China. Nonlinear mixed-effects modeling (NONMEM) was used for data analysis. The median prediction error (MPE), the distribution of prediction error (PE), and normalized prediction distribution errors (NPDE) were calculated and described. Predictive performance was evaluated by bias and accuracy. A total of 449 vancomycin concentrations from 397 infected participants were used for external validation. The MPE of the three models from the Chinese population was less than 10%. Half of the models had an acceptable MPE. For patients with different site infections and different renal functions, each model differed in its predictive ability to some extent. The NPDE results showed that all models had an obvious bias. None of the models had good performance in both prediction- and simulation-based diagnostics. Carrying out sufficient external validation of the PPK model before clinical application is of utmost importance. In clinical practice, the model's population closest to the application population should be used.

Pharmacokinetic equations versus Bayesian guided vancomycin monitoring: Pharmacokinetic model and model-informed precision dosing trial simulations.

The recently released revised vancomycin consensus guideline endorsed area under the concentration‐time curve (AUC) guided monitoring. Means to AUC‐guided monitoring include pharmacokinetic (PK) equations and Bayesian software programs, with the latter approach being preferable. We aimed to evaluate the predictive performance of these two methods when monitoring using troughs or peaks and troughs at varying single or mixed dosing intervals (DIs), and evaluate the significance of satisfying underlying assumptions of steady‐state and model transferability. Methods included developing a vancomycin population PK model and conducting model‐informed precision dosing clinical trial simulations. A one‐compartment PK model with linear elimination, exponential between‐subject variability, and mixed (additive and proportional) residual error model resulted in the best model fit. Conducted simulations demonstrated that Bayesian‐guided AUC can, potentially, outperform that of equation‐based AUC predictions depending on the quality of model diagnostics and met assumptions. Ideally, Bayesian‐guided AUC predictive performance using a trough from the first DI was equivalent to that of PK equations using two measurements (peak and trough) from the fifth DI. Model transferability diagnostics can guide the selection of Bayesian priors but are not strong indicators of predictive performance. Mixed versus single fourth and/or fifth DI sampling seems indifferent. This study illustrated cases associated with the most reliable AUC predictions and showed that only proper Bayesian‐guided monitoring is always faster and more reliable than equations‐guided monitoring in pre‐steady‐state DIs in the absence of a loading dose. This supports rapid Bayesian monitoring using data as sparse and early as a trough at the first DI.

Clinical application of vancomycin population pharmacokinetics model in patients with hematological diseases and neutropenia.

To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases and neutropenia. Patients with hematological diseases and neutropenia were included in the PPK model study. Nonlinear mixed effect modeling approach (NONMEM) was used for model establishment. Monte Carlo simulation was carried out. A total of 74 patients were divided into model group and non‐model group for clinical application research. The model group was given the initial dose of 1g q8h, and the non‐model group was given 1g q12h as an empiric initial dosage. The follow‐up dose adjustments were made according to the concentration results. This two‐compartment model showed good stability and accuracy. The first trough concentration (C 0) and the compliance rate of the first C 0 were much higher in the model group than that in the non‐model group (14.30 ± 4.73 μg/ml and 59.38% vs. 8.02 ± 2.61 μg/ml, 35.71%). Less patients needed dose adjustments and fewer adjustment times in the model group than those in the non‐model group (12.50% and 0.13 ± 0.34 times vs. 50.00% and 0.61 ± 0.66 times). This suggested that for those patients who had a Creatinine clearance rate (CLCR) ≥ 90 ml/min/1.73 m2, the initial dose of 1g q8h may help to reach the target C 0 (10∼20 μg/ml) quickly. It also helped to reduce the times and number of patients who need dose adjustments. Our PPK model of vancomycin in patients with hematologic diseases and neutropenia can be used to shorten the time to reach the target concentration and reduce the number of dose adjustments.Clinical trial registration: Not applicable (Retrospective study).

Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Population Pharmacokinetics of Vancomycin and Meropenem in Pediatric Extracorporeal Membrane Oxygenation Support.

Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target.Design: Prospective, multicentric, population PK analysis.Setting: Two hospitals with pediatric intensive care unit.Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support.Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of >400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% > 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30–550) ml/min/1.73 m2. The median dose was 13.6 (range 10–15) mg/kg every 6–12 h and 40 mg/kg every 8–12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin.Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.