Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients

Abstract Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting in various concentrations. Pharmacokinetic studies are therefore needed to define the optimal dosing regimen.

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

Antibiotics ◽

10.3390/antibiotics10050507 ◽

2021 ◽

Vol 10 (5) ◽

pp. 507

Author(s):

Alexandre Duong ◽

Chantale Simard ◽

Yi Le Wang ◽

David 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 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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What Are the Current Approaches to Optimising Antimicrobial Dosing in the Intensive Care Unit?

Pharmaceutics ◽

10.3390/pharmaceutics12070638 ◽

2020 ◽

Vol 12 (7) ◽

pp. 638

Author(s):

Ming G. Chai ◽

Menino O. Cotta ◽

Mohd H. Abdul-Aziz ◽

Jason A. Roberts

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Therapeutic Drug Monitoring ◽

Patient Outcomes ◽

Drug Monitoring ◽

Point Of Care ◽

Statistical Modelling ◽

Therapeutic Drug ◽

Dosing Regimens ◽

Point Of Care System

Antimicrobial dosing in the intensive care unit (ICU) can be problematic due to various challenges including unique physiological changes observed in critically ill patients and the presence of pathogens with reduced susceptibility. These challenges result in reduced likelihood of standard antimicrobial dosing regimens achieving target exposures associated with optimal patient outcomes. Therefore, the aim of this review is to explore the various methods for optimisation of antimicrobial dosing in ICU patients. Dosing nomograms developed from pharmacokinetic/statistical models and therapeutic drug monitoring are commonly used. However, recent advances in mathematical and statistical modelling have resulted in the development of novel dosing software that utilise Bayesian forecasting and/or artificial intelligence. These programs utilise therapeutic drug monitoring results to further personalise antimicrobial therapy based on each patient’s clinical characteristics. Studies quantifying the clinical and cost benefits associated with dosing software are required before widespread use as a point-of-care system can be justified.

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A retrospective analysis using Monte Carlo simulation to evaluate recommended ceftazidime dosing regimens in healthy volunteers, patients with cystic fibrosis, and patients in the intensive care unit

Clinical Therapeutics ◽

10.1016/j.clinthera.2005.06.013 ◽

2005 ◽

Vol 27 (6) ◽

pp. 762-772 ◽

Cited By ~ 44

Author(s):

Johan W. Mouton ◽

Nieko Punt ◽

Alexander A. Vinks

Keyword(s):

Cystic Fibrosis ◽

Intensive Care Unit ◽

Monte Carlo Simulation ◽

Monte Carlo ◽

Intensive Care ◽

Healthy Volunteers ◽

Retrospective Analysis ◽

Dosing Regimens

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Protecting Participants of Clinical Trials Conducted in the Intensive Care Unit

Journal of Intensive Care Medicine ◽

10.1177/0885066610390867 ◽

2011 ◽

Vol 26 (4) ◽

pp. 237-249 ◽

Cited By ~ 12

Author(s):

Brigid M. Flanagan ◽

Sean Philpott ◽

Martin A. Strosberg

Keyword(s):

Intensive Care Unit ◽

Clinical Trials ◽

Intensive Care

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Amantadine Can be Used as a Drug for SARS-Cov-2 Treatment?

Coronaviruses ◽

10.2174/2666796701999200713192912 ◽

2020 ◽

Vol 01 ◽

Author(s):

Zeynep Gunes Ozunal ◽

Sevki Sahin

Keyword(s):

Intensive Care Unit ◽

Clinical Trials ◽

Intensive Care ◽

Respiratory Failure ◽

Nmda Receptor ◽

Antiviral Drug ◽

Phase Iii ◽

Supportive Treatment ◽

Antagonistic Effects ◽

Phase Iii Clinical Trials

: Coronavirus Disease 2019 (COVID-19) infection, the pandemics, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has any known effective radical pharmacotherapy, just supportive approach at present. Amantadine is a drug used in Parkinson’s disease and other parkinsonisms; and is known to increase indirectly dopamine by antagonistic effects at the N-methyl-D-aspartate (NMDA) receptor by increasing the release and blocking the reuptake of dopamine. Initially, amantadine was approved as an antiviral drug. We hypothesize that if amantadine considered both antiviral, immunological and neurostimulant effects might be useful in the supportive treatment of SARS-CoV-2 cases, especially those who developed acute respiratory failure with decreased vigilance and monitored in the intensive care unit. Further phase III clinical trials are needed.

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1234 Prognosis of patients enrolled in phase I clinical trials admitted in intensive care unit

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(09)70446-x ◽

2009 ◽

Vol 7 (2) ◽

pp. 130-131

Author(s):

Y. Loriot ◽

C. Massard ◽

C. Moldovan ◽

C. Ferte ◽

C. Gomez-Roca ◽

...

Keyword(s):

Intensive Care Unit ◽

Clinical Trials ◽

Intensive Care ◽

Phase I ◽

Phase I Clinical Trials

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Assessment of Empiric Vancomycin Regimen in the Neonatal Intensive Care Unit

The Canadian Journal of Hospital Pharmacy ◽

10.4212/cjhp.v72i3.2901 ◽

2019 ◽

Vol 72 (3) ◽

Cited By ~ 1

Author(s):

Ruthdol Ywaya ◽

Brandi Newby

Keyword(s):

Intensive Care Unit ◽

Intensive Care ◽

Neonatal Intensive Care Unit ◽

Neonatal Intensive Care ◽

Culture Result ◽

Dosing Regimen ◽

Clinical Resolution ◽

Negative Culture ◽

Trough Levels ◽

Vancomycin Level

ABSTRACT Background: Vancomycin is used to treat serious gram-positive infections in neonates. Currently, there is no consensus on the preferred empiric dosing regimen or target trough vancomycin levels for neonates. The current Fraser Health empiric dosing regimen, implemented in 2010, was designed to achieve target trough levels of 5 to 15 mg/L. Objectives: To determine the percentage of neonates receiving vancomycin in whom target trough levels of 5 to 15 mg/L were achieved, to identify the times to negative culture result and clinical resolution, and to determine the incidence of nephrotoxicity. Methods: A chart review was completed for patients who had received vancomycin in the neonatal intensive care unit of either Surrey Memorial Hospital or Royal Columbian Hospital from June 2012 to May 2017 and for whom at least 1 interpretable vancomycin level was available. Results: A total of 87 vancomycin encounters (in 78 neonates) were identified in which the drug had been given according to the Fraser Health empiric dosing regimen. Target trough vancomycin level (5 to 15 mg/L) was achieved in 75% of these encounters. The mean times to negative culture result and clinical resolution were 5 and 6 days, respectively. There was no statistically significant correlation between vancomycin level and time to clinical resolution (rs = 0.366, p = 0.072). Among cases in which the trough vancomycin level exceeded 15 mg/L, the incidence of nephrotoxicity was 22% (4/18). Conclusions: The current Fraser Health empiric dosing regimen for vancomycin achieved target trough levels of the drug for most neonates in this study. Targeting trough levels less than 15 mg/L when appropriate to the infection type may limit nephrotoxicity associated with vancomycin in neonates. Further studies are needed to evaluate the clinical significance of various vancomycin levels.RÉSUMÉ Contexte : La vancomycine est utilisée dans le traitement d’infections graves à bactéries à Gram positif chez le nouveau-né. Il n’y a pour l’instant pas de consensus quant à la posologie empirique ou aux concentrations minimales visées de vancomycine à privilégier chez le nouveau-né. La posologie empirique actuelle de la Fraser Health, instaurée en 2010, visait des concentrations minimales de 5 à 15 mg/L. Objectifs : Déterminer le pourcentage de nouveau-nés ayant reçu les concentrations minimales visées de 5 à 15 mg/L de vancomycine, établir le temps nécessaire à l’obtention d’un résultat de culture négatif et celui nécessaire à la disparition clinique des symptômes et déterminer l’incidence de la néphrotoxicité.Méthodes : Les investigateurs ont analysé des dossiers de patients ayant reçu de la vancomycine pendant leur séjour à l’unité de soins intensifs néonatals du Surrey Memorial Hospital ou du Royal Columbian Hospital entre juin 2012 et mai 2017, qui mentionnaient au moins une concentration de vancomycine interprétable. Résultats : Ils ont répertorié 87 traitements de vancomycine (chez 78 nouveau-nés) administrés selon la posologie empirique de la Fraser Health. Les concentrations minimales visées de 5 à 15 mg/L ont été atteintes dans 75 % de ces traitements. Le temps moyen nécessaire à l’obtention d’un résultat de culture négatif ou à la disparition clinique des symptômes était respectivement de cinq et de six jours. Aucune corrélation statistiquement significative entre les concentrations de vancomycine et le temps nécessaire à la disparition clinique des symptômes n’a été relevée (rs = 0,366, p = 0,072). Parmi les cas où les concentrations minimales de vancomycine dépassaient 15 mg/L, l’incidence de néphrotoxicité était de 22 % (4/18). Conclusions : La posologie empirique de vancomycine actuellement en place à la Fraser Health a permis d’atteindre les concentrations minimales visées de médicament pour la plupart des nouveau-nés de la présente étude. Cibler des concentrations minimales de moins de 15 mg/L lorsque cela est pertinent en fonction du type d’infection pourrait limiter le nombre de cas de néphrotoxicité associés à la vancomycine chez les nouveau-nés. De plus amples études sont nécessaires pour évaluer la portée clinique de différentes concentrations de vancomycine.

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