Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

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1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1437 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S574-S575

Author(s):

Jiajun Liu ◽

Michael Neely ◽

Jeffrey Lipman ◽

Fekade B Sime ◽

Jason Roberts ◽

...

Keyword(s):

Rate Constant ◽

Pediatric Patients ◽

Validation Cohort ◽

External Validation ◽

Compartment Model ◽

Volume Of Distribution ◽

Information Criteria ◽

Population Pharmacokinetic ◽

Final Model ◽

Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

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Population pharmacokinetic modeling and clinical application of vancomycin in Chinese patients hospitalized in intensive care units

Scientific Reports ◽

10.1038/s41598-021-82312-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhong Lin ◽

Dan-yang Chen ◽

Yan-Wu Zhu ◽

Zheng-li Jiang ◽

Ke Cui ◽

...

Keyword(s):

Intensive Care ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

External Validation ◽

Chinese Patients ◽

Target Range ◽

Population Pharmacokinetic ◽

Icu Patients ◽

Final Model ◽

Trough Concentrations

AbstractManagement of vancomycin administration for intensive care units (ICU) patients remains a challenge. The aim of this study was to describe a population pharmacokinetic model of vancomycin for optimizing the dose regimen for ICU patients. We prospectively enrolled 466 vancomycin-treated patients hospitalized in the ICU, collected trough or approach peak blood samples of vancomycin and recorded corresponding clinical information from July 2015 to December 2017 at Tai Zhou Hospital of Zhejiang Province. The pharmacokinetics of vancomycin was analyzed by nonlinear mixed effects modeling with Kinetica software. Internal and external validation was evaluated by the maximum likelihood method. Then, the individual dosing regimens of the 92 patients hospitalized in the ICU whose steady state trough concentrations exceeded the target range (10–20 μg/ml) were adjusted by the Bayes feedback method. The final population pharmacokinetic model show that clearance rate (CL) of vancomycin will be raised under the conditions of dopamine combined treatment, severe burn status (Burn-S) and increased total body weight (TBW), but reduced under the conditions of increased serum creatinine (Cr) and continuous renal replacement therapy status; Meanwhile, the apparent distribution volume (V) of vancomycin will be enhanced under the terms of increased TBW, however decreased under the terms of increased age and Cr. The population pharmacokinetic parameters (CL and V) according to the final model were 3.16 (95%CI 2.83, 3.40) L/h and 60.71 (95%CI 53.15, 67.46). The mean absolute prediction error for external validation by the final model was 12.61% (95CI 8.77%, 16.45%). Finally, the prediction accuracy of 90.21% of the patients’ detected trough concentrations that were distributed in the target range of 10–20 μg/ml after dosing adjustment was found to be adequate. There is significant heterogeneity in the CL and V of vancomycin in ICU patients. The constructed model is sufficiently precise for the Bayesian dose prediction of vancomycin concentrations for the population of ICU Chinese patients.

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Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽

10.3390/pharmaceutics12010054 ◽

2020 ◽

Vol 12 (1) ◽

pp. 54 ◽

Cited By ~ 2

Author(s):

Amaia Soraluce ◽

Helena Barrasa ◽

Eduardo Asín-Prieto ◽

Jose Ángel Sánchez-Izquierdo ◽

Javier Maynar ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Standard Dose ◽

Compartment Model ◽

Antimicrobial Treatment ◽

Population Pharmacokinetic ◽

Renal Replacement Therapies ◽

Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01361-08 ◽

2009 ◽

Vol 53 (8) ◽

pp. 3430-3436 ◽

Cited By ~ 333

Author(s):

D. Plachouras ◽

M. Karvanen ◽

L. E. Friberg ◽

E. Papadomichelakis ◽

A. Antoniadou ◽

...

Keyword(s):

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

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Advances and Controversies in Adult ICU Sedation, Part 1: An Overview of the Importance of Sedation and Agitation and Subjective Assessment Tools for Patient Evaluation

Hospital Pharmacy ◽

10.1177/001857870103601208 ◽

2001 ◽

Vol 36 (12) ◽

pp. 1266-1278

Author(s):

Gilles L. Fraser ◽

Richard Riker

Keyword(s):

Health Care ◽

Drug Therapy ◽

Critically Ill ◽

Subjective Assessment ◽

Assessment Tools ◽

Critically Ill Patient ◽

Patient Evaluation ◽

Icu Patients ◽

Icu Sedation ◽

The Impact

This feature examines the impact of pharmacologic interventions on the treatment of the critically ill patient—an area of health care that has become increasingly complex. It will review recent advances (including evolving and controversial data) in drug therapy for adult ICU patients and assess these new modalities in terms of clinical, humanistic, and economic outcomes. Direct questions or comments to Gil Fraser, PharmD, at [email protected] .

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Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz158 ◽

2019 ◽

Vol 74 (8) ◽

pp. 2128-2138 ◽

Cited By ~ 3

Author(s):

Evelyne Jacqz-Aigrain ◽

Stéphanie Leroux ◽

Alison H Thomson ◽

Karel Allegaert ◽

Edmund V Capparelli ◽

...

Keyword(s):

Meta Analysis ◽

Intermittent Infusion ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Dosing Regimen ◽

Blue Book ◽

Young Infants ◽

Optimal Dosing ◽

Two Compartment Model ◽

Postmenstrual Age

Abstract Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <35 weeks PMA and 15 mg/kg q8h if ≥35 weeks PMA) achieved the AUC0–24 target earlier than a standard ‘Blue Book’ dosage regimen in >89% of the treated patients. Conclusions The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.

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

10.20944/preprints202104.0416.v1 ◽

2021 ◽

Author(s):

Alexandre Duong ◽

Chantale Simard ◽

Yi Le Wang ◽

David R. Williamson ◽

Amélie Marsot

Keyword(s):

Intensive Care ◽

External Validation ◽

Compartment Model ◽

Dosing Regimen ◽

Mixed Effect ◽

Icu Patients ◽

Optimal Dosing ◽

Pubmed Database ◽

Dosing Regimens ◽

Significant Covariates

Background Although aminoglycosides are often used as treatment for Gram-Negative infections, optimal dosing regimens remains unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycosides’ pharmacokinetics in this population. Objective The review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in 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. Methods A literature search was conducted from 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, eleven and five models, respectively. Two-compartment model best described amikacin and tobramycin pharmacokinetics, whereas 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. Conclusion This review showed models developed for amikacin, from 2015 until now and for gentamicin and tobramycin from the past decades. Despite 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 aminoglycosides pharmacokinetics in ICU patients.

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Assessment of the nlmixr R-package for population pharmacokinetic modeling: A metformin case study

10.22541/au.163630727.72118368/v1 ◽

2021 ◽

Author(s):

Wen Yao Mak ◽

Qing Xi Ooi ◽

Cintia Cruz ◽

Irene Looi ◽

Kah Hay Yuen ◽

...

Keyword(s):

Compartment Model ◽

Stochastic Simulations ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Mixed Effect ◽

Flip Flop ◽

Final Model ◽

Elimination Phase ◽

Transit Compartment ◽

Terminal Elimination Phase

Aim: nlmixr offers first-order conditional estimation with or without interaction (FOCE or FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin’s population pharmacokinetics with flip-flop characteristics within nlmixr framework and investigated SAEM and FOCEi’s performance with respect to bias, precision, and robustness. Method: Compartmental pharmacokinetic models were fitted. The final model was determined based on the lowest objective function value and visual inspection of goodness-of-fit plots. To examine flip-flop pharmacokinetics, k_a values of a typical concentration-time profile based on the final model were perturbed and changes in the steepness of the terminal elimination phase were evaluated. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100-times and resultant changes evaluated. Results: A one-compartment model with transit compartment for absorption best described the data. At low n, Stirling’s approximation of n! over-approximated plasma concentration unlike the log-gamma function. Flip-flop pharmacokinetics were evident as the steepness of the terminal elimination phase changed with k_a. Mean rRMSE for fixed-effect parameters was 0.932. When initial estimates were perturbed, FOCEi estimates of k_a and food effect on k_a appeared bimodal and were upward biased. Discussion: nlmixr is reliable for NLMEM even if flip-flop is present but caution should be exercised when using Stirling’s approximation for n! in the transit compartment model. SAEM was marginally superior to FOCEi in bias and precision, but SAEM was superior against initial estimate perturbations.

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Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib

Pharmaceutics ◽

10.3390/pharmaceutics13050629 ◽

2021 ◽

Vol 13 (5) ◽

pp. 629

Author(s):

Ki Young Huh ◽

Sejung Hwang ◽

Sang Yeob Park ◽

Hye Jung Lim ◽

Miryung Jin ◽

...

Keyword(s):

Compartmental Analysis ◽

Optimal Dose ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Open Label ◽

Post Dose ◽

Multikinase Inhibitor ◽

Final Model ◽

Fasted State ◽

Second Period

Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar® 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar® 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar® 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.

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Cardiopulmonary Bypass Has Minimal Effects on the Pharmacokinetics of Fentanyl in Adults

Anesthesiology ◽

10.1097/00000542-200310000-00016 ◽

2003 ◽

Vol 99 (4) ◽

pp. 847-854 ◽

Cited By ~ 9

Author(s):

Robert J. Hudson ◽

Ian R. Thomson ◽

Rajive Jassal ◽

David J. Peterson ◽

Aaron D. Brown ◽

...

Keyword(s):

Cardiopulmonary Bypass ◽

Prediction Error ◽

Predictive Accuracy ◽

Predictive Ability ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Model Parameters ◽

Final Model ◽

Three Compartment Model

Background Although fentanyl has been widely used in cardiac anesthesia, no complete pharmacokinetic model that has assessed the effect of cardiopulmonary bypass (CPB) and that has adequate predictive accuracy has been defined. The aims of this investigation were to determine whether CPB had a clinically significant impact on fentanyl pharmacokinetics and to determine the simplest model that accurately predicts fentanyl concentrations during cardiac surgery using CPB. Methods Population pharmacokinetic modeling was applied to concentration-versus-time data from 61 patients undergoing coronary artery bypass grafting using CPB. Predictive ability of models was assessed by calculating bias (prediction error), accuracy (absolute prediction error), and measured:predicted concentration ratios versus time. The predictive ability of a simple three-compartment model with no covariates was initially compared to models with premedication (lorazepam vs. clonidine), sex, or weight as covariates. This simple model was then compared to 18 CPB-adjusted models that allowed for step changes in pharmacokinetic parameters at the start and/or end of CPB. The predictive ability of the final model was assessed prospectively in a second group of 29 patients. Results None of the covariate (premedication, sex, weight) models nor any of the CPB-adjusted models significantly improved prediction error or absolute prediction error, compared to the simple three-compartment model. Thus, the simple three-compartment model was selected as the final model. Prospective assessment of this model yielded a median prediction error of +3.8%, with a median absolute prediction error of 15.8%. The model parameters were as follows: V1, 14.4 l; V2, 36.4 l; V3, 169 l; Cl1, 0.82 l. min-1; Cl2, 2.31 l x min-1; Cl3, 1.35 l x min-1. Conclusions Compared to other factors that cause pharmacokinetic variability, the effect of CPB on fentanyl kinetics is clinically insignificant. A simple three-compartment model accurately predicts fentanyl concentrations throughout surgery using CPB.

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