TY  - JOUR
AU  - Milaković, Dragana
AU  - Kovačević, Tijana
AU  - Kovačević, Peđa
AU  - Barišić, Vedrana
AU  - Avram, Sanja
AU  - Dragić, Saša
AU  - Zlojutro, Biljana
AU  - Momčičević, Danica
AU  - Miljković, Branislava
AU  - Vučićević, Katarina
PY  - 2024
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5557
AB  - During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients’ individual PK parameters and corresponding concentration–time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.
PB  - MDPI
T2  - Pharmaceutics
T1  - Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing
VL  - 16
IS  - 2
DO  - 10.3390/pharmaceutics16020253
ER  - 

@article{
author = "Milaković, Dragana and Kovačević, Tijana and Kovačević, Peđa and Barišić, Vedrana and Avram, Sanja and Dragić, Saša and Zlojutro, Biljana and Momčičević, Danica and Miljković, Branislava and Vučićević, Katarina",
year = "2024",
abstract = "During veno-venous extracorporeal membrane oxygenation (vv ECMO) therapy, antimicrobial drugs are frequently used, and appropriate dosing is challenging due to there being limited data to support the dosage. Linezolid is effective against multidrug-resistant Gram-positive pathogens frequently isolated in ECMO patients. In total, 53 steady-state linezolid levels were obtained following 600 mg intravenous (IV) injections every 8 h, and these were used to develop a population pharmacokinetic (PopPK) model in patients with COVID-19-associated acute respiratory distress syndrome (CARDS) on vv ECMO. The data were analyzed using a nonlinear mixed-effects modelling approach. Monte Carlo simulation generated 5000 patients’ individual PK parameters and corresponding concentration–time profiles using the PopPK model, following the administration of 600 mg/8 h (a higher-than-standard dosing) and 600 mg/12 h (standard). The probabilities of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) and the cumulative fraction of responses (CFR) for three pathogens were calculated and compared between the two dosing scenarios. Linezolid 600 mg/8 h was predicted to achieve greater than or equal to 85%Tf>MIC in at least 90% of the patients with CARDS on vv ECMO compared to only approximately two thirds of the patients after dosing every 12 h at a minimal inhibitory concentration (MIC) of 2 mg/L. In addition, for the same MIC, fAUC24/MIC ≥ 80 was achieved in almost three times the number of patients following an 8-h versus a 12-h interval. PopPK simulation predicted that a significantly higher proportion of the patients with CARDS on vv ECMO would achieve the PK/PD targets following the 8-h dosing interval compared to standard linezolid dosing. Nevertheless, the safety concern, in particular, for thrombocytopenia, with higher-than-standard linezolid dosage is reasonable, and consequently, monitoring is essential.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing",
volume = "16",
number = "2",
doi = "10.3390/pharmaceutics16020253"
}

Milaković, D., Kovačević, T., Kovačević, P., Barišić, V., Avram, S., Dragić, S., Zlojutro, B., Momčičević, D., Miljković, B.,& Vučićević, K.. (2024). Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing. in Pharmaceutics
MDPI., 16(2).
https://doi.org/10.3390/pharmaceutics16020253

Milaković D, Kovačević T, Kovačević P, Barišić V, Avram S, Dragić S, Zlojutro B, Momčičević D, Miljković B, Vučićević K. Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing. in Pharmaceutics. 2024;16(2).
doi:10.3390/pharmaceutics16020253 .

Milaković, Dragana, Kovačević, Tijana, Kovačević, Peđa, Barišić, Vedrana, Avram, Sanja, Dragić, Saša, Zlojutro, Biljana, Momčičević, Danica, Miljković, Branislava, Vučićević, Katarina, "Population Pharmacokinetic Model of Linezolid and Probability of Target Attainment in Patients with COVID-19-Associated Acute Respiratory Distress Syndrome on Veno-Venous Extracorporeal Membrane Oxygenation—A Step toward Correct Dosing" in Pharmaceutics, 16, no. 2 (2024),
https://doi.org/10.3390/pharmaceutics16020253 . .

TY  - JOUR
AU  - Kovačević, Tijana
AU  - Miljković, Branislava
AU  - Kovačević, Peđa
AU  - Dragić, Saša
AU  - Momčićević, Danica
AU  - Avram, Sanja
AU  - Jovanović, Marija
AU  - Vučićević, Katarina
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4826
AB  - Purpose: The present study aimed to establish a population pharmacokinetic model of vancomycin, including adult critically ill septic patients, with normal and impaired renal function.

Materials and methods: A prospective analysis of 146 concentrations from 73 adult critically ill septic patients treated with 1-h intravenous infusion of vancomycin were included in the study. A nonlinear mixed effects modeling (NONMEM) approach was applied for data analysis and evaluation of the final model. The influence of creatinine clearance calculated by the Cockcroft-Gault equation (CrCl), and other potential covariates on vancomycin clearance (CL) were evaluated.

Results: The final one-compartment pharmacokinetic model includes the effect of CrCl on CL. Population pharmacokinetic values for a typical subject were estimated at 0.024 l/h for CL dependent on renal function (CLCrCl), 1.93 l/h for residual portion of CL (not dependent on renal function), and 0.511 l/kg for volume of distribution (V). According to the final model, for patients with CrCl = 120 ml/min, the median vancomycin total CL is 4.81 l/h, while CrCl-dependent fraction accounts for approximately 60% of CL.

Conclusions: The developed population vancomycin model may be used in estimating individual CL for adult critically ill septic patients, and could be applied for individualizing dosage regimens taking into account the continuous effect of CrCl.
PB  - Elsevier Inc.
T2  - Journal of Critical Care
T1  - Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients
VL  - 55
SP  - 116
EP  - 121
DO  - 10.1016/j.jcrc.2019.10.012
ER  - 

@article{
author = "Kovačević, Tijana and Miljković, Branislava and Kovačević, Peđa and Dragić, Saša and Momčićević, Danica and Avram, Sanja and Jovanović, Marija and Vučićević, Katarina",
year = "2020",
abstract = "Purpose: The present study aimed to establish a population pharmacokinetic model of vancomycin, including adult critically ill septic patients, with normal and impaired renal function.

Materials and methods: A prospective analysis of 146 concentrations from 73 adult critically ill septic patients treated with 1-h intravenous infusion of vancomycin were included in the study. A nonlinear mixed effects modeling (NONMEM) approach was applied for data analysis and evaluation of the final model. The influence of creatinine clearance calculated by the Cockcroft-Gault equation (CrCl), and other potential covariates on vancomycin clearance (CL) were evaluated.

Results: The final one-compartment pharmacokinetic model includes the effect of CrCl on CL. Population pharmacokinetic values for a typical subject were estimated at 0.024 l/h for CL dependent on renal function (CLCrCl), 1.93 l/h for residual portion of CL (not dependent on renal function), and 0.511 l/kg for volume of distribution (V). According to the final model, for patients with CrCl = 120 ml/min, the median vancomycin total CL is 4.81 l/h, while CrCl-dependent fraction accounts for approximately 60% of CL.

Conclusions: The developed population vancomycin model may be used in estimating individual CL for adult critically ill septic patients, and could be applied for individualizing dosage regimens taking into account the continuous effect of CrCl.",
publisher = "Elsevier Inc.",
journal = "Journal of Critical Care",
title = "Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients",
volume = "55",
pages = "116-121",
doi = "10.1016/j.jcrc.2019.10.012"
}

Kovačević, T., Miljković, B., Kovačević, P., Dragić, S., Momčićević, D., Avram, S., Jovanović, M.,& Vučićević, K.. (2020). Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients. in Journal of Critical Care
Elsevier Inc.., 55, 116-121.
https://doi.org/10.1016/j.jcrc.2019.10.012

Kovačević T, Miljković B, Kovačević P, Dragić S, Momčićević D, Avram S, Jovanović M, Vučićević K. Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients. in Journal of Critical Care. 2020;55:116-121.
doi:10.1016/j.jcrc.2019.10.012 .

Kovačević, Tijana, Miljković, Branislava, Kovačević, Peđa, Dragić, Saša, Momčićević, Danica, Avram, Sanja, Jovanović, Marija, Vučićević, Katarina, "Population pharmacokinetic model of Vancomycin based on therapeutic drug monitoring data in critically ill septic patients" in Journal of Critical Care, 55 (2020):116-121,
https://doi.org/10.1016/j.jcrc.2019.10.012 . .