High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints

Anouk M E Jansen; Rob Ter Heine; Paul E Verweij; Roger J M Brüggemann

doi:10.1007/s40262-023-01311-w

High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints

Clin Pharmacokinet. 2023 Dec;62(12):1695-1699. doi: 10.1007/s40262-023-01311-w. Epub 2023 Oct 11.

Authors

Anouk M E Jansen^{1

2}, Rob Ter Heine³, Paul E Verweij^{4

5}, Roger J M Brüggemann^{3

4}

Affiliations

¹ Department of Pharmacy, Radboud university Medical Center, Radboud Institute for Medical Innovations, Geert Grooteplein-Zuid 10, Postbox 9101, 6500 HB, Nijmegen, The Netherlands. anouk.me.jansen@radboudumc.nl.
² Radboud University Medical Center-Canisius Wilhelmina Ziekenhuis Center of Expertise for Mycology, Nijmegen, The Netherlands. anouk.me.jansen@radboudumc.nl.
³ Department of Pharmacy, Radboud university Medical Center, Radboud Institute for Medical Innovations, Geert Grooteplein-Zuid 10, Postbox 9101, 6500 HB, Nijmegen, The Netherlands.
⁴ Radboud University Medical Center-Canisius Wilhelmina Ziekenhuis Center of Expertise for Mycology, Nijmegen, The Netherlands.
⁵ Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Medical Innovations, Nijmegen, The Netherlands.

Abstract

Isavuconazole exposure-response relationships have been studied with a focus on total rather than unbound exposure, assuming a constant unbound fraction of 1%. We observed a median (range) unbound fraction of 1.59% (0.42-5.30%) in patients. This highly variable protein binding asks for re-evaluation of current pharmacokinetic and pharmacodynamic targets for isavuconazole.

MeSH terms

Humans
Nitriles* / pharmacokinetics
Protein Binding
Pyridines* / pharmacokinetics
Pyridines* / therapeutic use
Triazoles / pharmacokinetics

Substances

isavuconazole
Nitriles
Pyridines
Triazoles