Isavuconazole Pharmacokinetics and Pharmacodynamics in Children
Hirsh Elhence1, Kanokporn Mongkolrattanothai1,2, Sindhu Mohandas1,2
1Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Insights
Isavuconazole dosing in children shows similar concentrations to adults. Effective exposure can be achieved with 10 mg/kg/dose, but mortality is linked to low AUC and high liver enzymes.
Area of Science:
- Pharmacology and Therapeutics
- Pediatric Infectious Diseases
Background:
- Isavuconazole, a broad-spectrum azole antifungal, lacks approval for pediatric use.
- Understanding isavuconazole pharmacokinetics and safety in children is crucial for expanding its therapeutic applications.
Purpose of the Study:
- To evaluate isavuconazole use, therapeutic drug monitoring, and population pharmacokinetics in pediatric patients.
- To determine optimal dosing strategies and identify factors associated with mortality and hepatotoxicity.
Main Methods:
- Retrospective, single-center review of 26 pediatric patients receiving isavuconazole.
- Extraction of demographic, dosing, concentration, mortality, and hepatotoxicity data.
- Construction of a nonparametric population pharmacokinetic model using Pmetrics.
Main Results:
- Predicted steady-state isavuconazole concentrations were comparable to adult and previous pediatric reports.
- Simulations supported a dosing regimen of 10 mg/kg/dose every 8 hours for 2 days, followed by daily maintenance, matching adult exposures.
- Attributable mortality was associated with lower AUC (< 60 mg*h/L) and higher AST/ALT with trough concentrations (> 5 mg/L).
Conclusions:
- The proposed pediatric dosing regimen for isavuconazole can achieve effective exposures.
- Therapeutic drug monitoring, particularly AUC estimation, is important for optimizing outcomes and minimizing toxicity.
- Further research is warranted to establish definitive pediatric dosing guidelines and safety profiles.
Abstract:
Isavuconazole is a broad-spectrum azole anti-fungal not yet approved in children. We conducted a retrospective, single-center review of isavuconazole use and routine therapeutic drug monitoring in pediatric patients, extracting demographic, dosing, concentration, mortality and hepatoxicity data. We constructed a nonparametric population model using Pmetrics. Of 26 patients, 19 (73%) were male. The mean (SD) age and weight were 12.7 (5.5) years and 50.9 (26.8) kg. Eighty percent received between 9.7 and 10.6 mg/kg per dose. Ten (38%) subjects had proven fungal disease and eight (31%) had probable disease, mostly with Candida and Aspergillus spp. The predicted steady-state isavuconazole concentrations in our patients were similar to previous reports in children and adults, and simulations with the proposed dosing of 10 mg/kg/dose every 8 h for 2 days followed by once daily maintenance matched effective adult exposures. Attributable mortality (5 of 11 deaths) was associated with steady-state daily AUC < 60 mg∗h/L and higher AST/ALT with trough concentrations > 5 mg/L. Neither dose nor trough alone correlated well with AUC, but AUC can be estimated with one sample 10 h after the first maintenance dose or a trough concentration, if combined with a Bayesian approach or a peak and trough without a Bayesian approach.
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