Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified...

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Published in:	Antimicrobial agents and chemotherapy Vol. 65; no. 8; p. e0029021
Main Authors:	Arrieta, Antonio C, Neely, Michael, Day, J Christopher, Rheingold, Susan R, Sue, Paul K, Muller, William J, Danziger-Isakov, Lara A, Chu, Julie, Yildirim, Inci, McComsey, Grace A, Frangoul, Haydar A, Chen, Tempe K, Statler, Victoria A, Steinbach, William J, Yin, Dwight E, Hamed, Kamal, Jones, Mark E, Lademacher, Christopher, Desai, Amit, Micklus, Kelley, Phillips, Desiree Leiva, Kovanda, Laura L, Walsh, Thomas J
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 16-07-2021
Subjects:	Administration, Oral Adolescent Child Child, Preschool Clinical Therapeutics Humans Infant Invasive Fungal Infections - drug therapy Nitriles - therapeutic use Pyridines - adverse effects Triazoles - therapeutic use isavuconazole invasive fungal infections pediatric population pharmacokinetics triazole
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Summary:	Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (i.v.) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg body weight (maximum, 372 mg) isavuconazonium sulfate either i.v. or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric i.v. and oral data plus i.v. data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration-time curve at steady state (AUC ) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUC range, 60 to 233 μg · h/ml) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following i.v. or oral administration, respectively. Intravenous and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults. (This study has been registered at ClinicalTrials.gov under identifier NCT03241550).
Bibliography:	Present address: Dwight E. Yin, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA. Citation Arrieta AC, Neely M, Day JC, Rheingold SR, Sue PK, Muller WJ, Danziger-Isakov LA, Chu J, Yildirim I, McComsey GA, Frangoul HA, Chen TK, Statler VA, Steinbach WJ, Yin DE, Hamed K, Jones ME, Lademacher C, Desai A, Micklus K, Phillips DL, Kovanda LL, Walsh TJ. 2021. Safety, tolerability, and population pharmacokinetics of intravenous and oral isavuconazonium sulfate in pediatric patients. Antimicrob Agents Chemother 65:e00290-21. https://doi.org/10.1128/AAC.00290-21.
ISSN:	0066-4804 1098-6596
DOI:	10.1128/AAC.00290-21