Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube.

Autor:	Bury D; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands., Wolfs TFW; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Infectious Diseases, Wilhelmina Children's Hospital/University Medical Center Utrecht, Utrecht, The Netherlands.; Department of Infectious Diseases, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands., Ter Heine R; Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands., Muilwijk EW; Department of Pharmacy, Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands., van der Elst KCM; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands., Tissing WJE; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands., Brüggemann RJM; Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.; Department of Pharmacy, Radboud University Medical Center, Radboud Institute for Medical Innovation, Nijmegen, The Netherlands.; Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	The Journal of antimicrobial chemotherapy [J Antimicrob Chemother] 2023 Dec 01; Vol. 78 (12), pp. 2886-2889.
DOI:	10.1093/jac/dkad324
Abstrakt:	Objectives: To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics. Methods: In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily). Results: Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%. Conclusions: This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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