Background: Best practice to establish dosage regimens for first-in-pediatric clinical trials requires knowledge of efficacious and safe exposures in adults.
Methods: Pediatric equivalent doses were predicted for patients aged 6 months and <18 years using physiologically based pharmacokinetic (PBPK) modeling, and compared to predictions by allometric scaling. All simulations were completed using PK-Sim®, which implements a whole-body PBPK model with 15 organs and appropriate maturation of anatomical and physiological parameters for children. The adult PBPK model was built using knowledge of drug physico-chemistry and clearance partitioning (CYP3A4, CYP3A5, glomerular filtration). PK data following IV (40, 80, 160 mg 60-min infusion) and oral (100, 200, 400 mg capsule) doses in adults were used for initial model development. This model was validated by matching observed adult concentrations after multiple oral 200 mg doses. From this adult model, a virtual pediatric population (n=4,600) from 6 months to <18 years was created. Simulations with the pediatric model assessed optimal doses of isavuconazonium sulfate based on age and weight to achieve at least a median steady-state daily area under the curve (AUCss) of 100 mg*h/L, and the majority below 230 mg*h/L. These targets were derived from efficacy and safety data in clinical trials with adults.
Results: As shown in the Figure, an isavuconazonium sulfate dose of 10 mg/kg is expected to result in AUCss within the target range for the majority of patients >1 year old, in agreement with that predicted by allometry for patients aged 2 17 years. For patients aged 6 months to 1 year, a dose of 6 mg/kg predicts comparable exposures.
Conclusion: A proposed isavuconazonium sulfate dose of 10 mg/kg administered every 8 h for the first 2 days and once daily thereafter is predicted to result in safe and efficacious steady state exposures in patients aged 117 years, similar to predictions from allometric scaling for patients aged 217 years. For subjects aged 6 months to 1 year, a dose of 6 mg/kg is predicted to achieve similar exposures. These doses should be tested in clinical trials to confirm.
Figure: Box plot of predicted AUCss by age group for a 6 mg/kg dose (ages 6 months to <1 year) or 10 mg/kg dose (all other groups).
Astellas Pharma, Inc.:
C. Lademacher, Astellas Pharma, Inc.: Employee , Salary .
W. Hope, F2G: Grant Investigator and Scientific Advisor , Consulting fee and Research grant . Astellas: Grant Investigator and Investigator , Grant recipient and Research grant . Pfizer: Grant Investigator , Research support . Gilead: Consultant and Scientific Advisor , Consulting fee .
M. Neely, None
P. Bonate, Astellas Pharma, Inc.: Employee , Salary .
A. Edginton, Astellas Pharma Global Development, Inc.: Independent Contractor , Consulting fee .