PHARMACOLOGY OF ANTIFUNGALS USED IN CHILDREN

George R Thompson, III, MD: Those are really interesting outcomes. We’ve used a lot of isavuconazole over the last few years with good results. It certainly has fewer drug interactions. Isavuconazole also allows us to minimize QTC prolongation issues, which are often problematic for us with other azoles for some of our patients.31 They’re on lots of anti-nausea drugs that cause QTC prolongation and potentially quinolones. Is that something you deal with in the pediatric population?

Antonio Arrieta, MD: Not at the same frequency as you would find in the adult population. At our center, we did monitor the patients in the phase 2 isavuconazole study, and there were no cases of QTc prolongation. But anytime we start an azole agent, we alert our pharmacists and our intensivists to start looking for potential interactions—start monitoring. Sometimes hypertension in a patient receiving posaconazole could alert us to pseudohyperaldosteronism as a consequence or as a complication.31,32 Of course, we have to pay attention to interactions between the triazoles and cyclosporine, tacrolimus, and other agents used to prevent or manage GVHD. We have to watch the levels of these drugs, because they can be raised or lowered when given with triazoles, depending on the nature of the interaction. Sometimes we see nephrotoxicity associated with cyclosporine in the patient who has been started on the azole agent. Some azoles have stronger interaction with these agents, particularly voriconazole.

George R Thompson, III, MD: Overall, that’s our experience as well with isavuconazole. It seems to be the cleanest of the triazoles anecdotally. Then, there’s been lots of recommendations for the patients who either are going to be started on therapy or who’ve been on therapy. Do they need therapeutic drug monitoring (TDM)? We know the answer for that for voriconazole; we kind of know the answer for that with posaconazole, but we have a little bit less guidance with isavuconazole. It seems patients absorb it very well. They have really good levels, but again, that’s mostly the adult literature.33 How about in the pediatric population? Are there serum levels fairly predictable? What does it look like?

Antonio Arrieta, MD: This is an area of great interest to me. A 1-year-old child is very different compared to a 14-year-old, particularly if they are 14 and weigh 120 kilos. So, it is tricky. Some of these patients are going to reach the weight at which they will have to transition to adult doses based on maximum dose, but they still have pediatric physiology, so they may clear the agent faster than a comparable adult with the same weight.

When we conducted this phase 2 study, we set the target plasma isavuconazole exposure range (AUCSS) at 60 to 233 mg•h/L (Figure 6). These were previously established target exposure ranges extrapolated from the isavuconazole adult studies.29 The lower limit of this range delineated the 25th percentile of AUCSS from the Phase 3 SECURE study. This is shown as the light orange dotted line at the bottom of the figure. The upper limit of this range was the minimum AUC from 0 to 24 h (AUC0–24) from an adult safety study that used a supratherapeutic dose (1116 mg) to evaluate the risk of prolonged QT interval. This is shown as the green dotted line at the top.

As shown in Figure 6, it was more difficult to reach the target range in the younger patients. Indeed, 5/15 (33.3%) of patients in the 1 to <6 years of age group had an AUCss under the 60 mg•hr/L target. This was driven mostly by the patients <3 years of age. This is the rationale for the higher isavuconazole dosing of 15 mg/kg in younger patients. Note that none of the patients had an AUCss above the upper target exposure threshold.29

Figure 6. Area-under-the-curve steady state (AUCss) values for isavuconazole based on age.29

The target plasma isavuconazole exposure range (AUCSS) was 60 to 233 mg•h/L.29 Reproduced from the open-source article Segers H, Deville JG, Muller WJ, et al. Safety, outcomes, and pharmacokinetics of isavuc treatment for invasive fungal diseases in pediatric patients: a non-comparative phase 2 trial. Antimicrob Agents Chemother. 2024;68(12):e0048424. doi:10.1128/aac.00484-24, licensed by Creative Commons 4.0.

TABLE OF CONTENTS

Faculty

George R. Thompson, III, MD

Professor of Medicine
University of California, Davis, School of Medicine
Sacramento, California

Antonio C. Arrieta, MD

Division Chief
Pediatric Infectious Diseases
Children’s Hospital of Orange County (CHOC)
Orange, California

MyCARE thanks Astellas for sponsoring this activity.

Copyright © 2025. ALL RIGHTS RESERVED. MyCARE Foundation. Astellas-sponsored, MA-MM-14973. May 2025. ASTELLAS and the Flying Star Logo are registered trademarks of Astellas Pharma Inc. Used with permission.