Safety, tolerability, and population pharmacokinetics of intravenous and oral isavuconazonium sulfate in pediatric patients

Antonio C. Arrieta*, Michael Neely, J. Christopher Day, Susan R. Rheingold, Paul K. Sue, William J. Muller, Lara A. Danziger-Isakov, Julie Chu, Inci Yildirim, Grace A. McComsey, Haydar A. Frangoul, Tempe K. Chen, Victoria A. Statler, William J. Steinbach, Dwight E. Yin, Kamal Hamed, Mark E. Jones, Christopher Lademacher, Amit Desai, Kelley MicklusDesiree Leiva Phillips, Laura L. Kovanda, Thomas J. Walsh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 (AUCSS) was predicted for pediatric patients using 1,000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range, 60 to 233 mg 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

Original languageEnglish (US)
Article numbere00290
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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