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
Аутори
Milaković, DraganaKovačević, Tijana
Kovačević, Peđa
Barišić, Vedrana
Avram, Sanja
Dragić, Saša
Zlojutro, Biljana
Momčičević, Danica
Miljković, Branislava
Vučićević, Katarina
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
COVID-19 / dosing / ECMO / linezolid / population pharmacokinetics / PTAИзвор:
Pharmaceutics, 2024, 16, 2Издавач:
- MDPI
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200161 (Универзитет у Београду, Фармацеутски факултет) (RS-MESTD-inst-2020-200161)
- In 2022 research grant support was approved for this study by the Zoll foundation.
DOI: 10.3390/pharmaceutics16020253
ISSN: 1999-4923
PubMed: 38399307
WoS: 001177068900001
Scopus: 2-s2.0-85186111657
Институција/група
PharmacyTY - 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 . .