Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
accepted:
04
09
2023
medline:
29
11
2023
pubmed:
11
10
2023
entrez:
11
10
2023
Statut:
ppublish
Résumé
Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy. A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach. Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure. In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population. ClinicalTrials.gov identifier: NCT04777058.
Sections du résumé
BACKGROUND AND OBJECTIVES
OBJECTIVE
Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy.
METHODS
METHODS
A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach.
RESULTS
RESULTS
Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure.
CONCLUSIONS
CONCLUSIONS
In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population.
CLINICAL TRIAL REGISTRATION
BACKGROUND
ClinicalTrials.gov identifier: NCT04777058.
Identifiants
pubmed: 37819503
doi: 10.1007/s40262-023-01305-8
pii: 10.1007/s40262-023-01305-8
pmc: PMC10684418
doi:
Substances chimiques
Anti-Bacterial Agents
0
isavuconazole
60UTO373KE
Triazoles
0
Banques de données
ClinicalTrials.gov
['NCT04777058']
Types de publication
Multicenter Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1701-1711Informations de copyright
© 2023. The Author(s).
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