Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients.
Antimicrob Agents Chemother
; 65(8): e0029021, 2021 07 16.
Article
in En
| MEDLINE
| ID: mdl-34031051
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 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).
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triazoles
/
Invasive Fungal Infections
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Child
/
Child, preschool
/
Humans
/
Infant
Language:
En
Journal:
Antimicrob Agents Chemother
Year:
2021
Document type:
Article
Affiliation country:
United States