Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients
Background: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2786 |
| _version_ | 1827637272260902912 |
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| author | Noël Zahr Saik Urien Benoit Llopis Gaëlle Noé Nadine Tissot Kevin Bihan Helga Junot Clémence Marin Bochra Mansour Charles-Edouard Luyt Alexandre Bleibtreu Christian Funck-Brentano |
| author_facet | Noël Zahr Saik Urien Benoit Llopis Gaëlle Noé Nadine Tissot Kevin Bihan Helga Junot Clémence Marin Bochra Mansour Charles-Edouard Luyt Alexandre Bleibtreu Christian Funck-Brentano |
| author_sort | Noël Zahr |
| collection | DOAJ |
| description | Background: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. Methods: We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. Results: A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant <i>Pseudomonas aeruginosa</i> infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CL<sub>U</sub>) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). Conclusion: This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy. |
| first_indexed | 2024-03-09T15:58:37Z |
| format | Article |
| id | doaj.art-abc567933a9640a2aa8229af8855b074 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:37Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-abc567933a9640a2aa8229af8855b0742023-11-24T17:22:00ZengMDPI AGPharmaceutics1999-49232022-12-011412278610.3390/pharmaceutics14122786Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill PatientsNoël Zahr0Saik Urien1Benoit Llopis2Gaëlle Noé3Nadine Tissot4Kevin Bihan5Helga Junot6Clémence Marin7Bochra Mansour8Charles-Edouard Luyt9Alexandre Bleibtreu10Christian Funck-Brentano11Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FranceUnité de Recherche Clinique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacy Department, Pitié-Salpêtrière Hospital, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FranceService de Médecine Intensive Réanimation, Institut de Cardiologie, AP-HP Sorbonne-Université, Pitié-Salpêtrière Hospital, 75013 Paris, FranceService de Maladies Infectieuses et Tropicales, Pitié-Salpêtrière Hospital, AP-HP Sorbonne Université, 75013 Paris, FrancePharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, FranceBackground: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. Methods: We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. Results: A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant <i>Pseudomonas aeruginosa</i> infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CL<sub>U</sub>) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). Conclusion: This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy.https://www.mdpi.com/1999-4923/14/12/2786cefiderocolpharmacokineticsPK/PDantibioticsdrug monitoring |
| spellingShingle | Noël Zahr Saik Urien Benoit Llopis Gaëlle Noé Nadine Tissot Kevin Bihan Helga Junot Clémence Marin Bochra Mansour Charles-Edouard Luyt Alexandre Bleibtreu Christian Funck-Brentano Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients Pharmaceutics cefiderocol pharmacokinetics PK/PD antibiotics drug monitoring |
| title | Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients |
| title_full | Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients |
| title_fullStr | Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients |
| title_full_unstemmed | Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients |
| title_short | Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients |
| title_sort | total and unbound pharmacokinetics of cefiderocol in critically ill patients |
| topic | cefiderocol pharmacokinetics PK/PD antibiotics drug monitoring |
| url | https://www.mdpi.com/1999-4923/14/12/2786 |
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