Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients
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
Affiliations
Noël Zahr
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Saik Urien
Unité de Recherche Clinique, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France
Benoit Llopis
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Gaëlle Noé
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Nadine Tissot
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Kevin Bihan
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Helga Junot
Pharmacy Department, Pitié-Salpêtrière Hospital, AP-HP Sorbonne Université, 75013 Paris, France
Clémence Marin
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Bochra Mansour
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
Charles-Edouard Luyt
Service de Médecine Intensive Réanimation, Institut de Cardiologie, AP-HP Sorbonne-Université, Pitié-Salpêtrière Hospital, 75013 Paris, France
Alexandre Bleibtreu
Service de Maladies Infectieuses et Tropicales, Pitié-Salpêtrière Hospital, AP-HP Sorbonne Université, 75013 Paris, France
Christian Funck-Brentano
Pharmacokinetics and Therapeutic Drug Monitoring Unit, Department of Pharmacology, Pitié-Salpêtrière Hospital, Inserm, CIC-1901, UMR-S 1166, AP-HP Sorbonne Université, 75013 Paris, France
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 Pseudomonas aeruginosa 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 (CLU) 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.
