Development of an Isavuconazole Physiologically-based Pharmacokinetic Model for Adult and Pediatric Populations

Isavuconazonium sulfate is the water-soluble prodrug of the active triazole antifungal agent isavuconazole. Isavuconazonium sulfate is approved for use as iv formulation in adult and pediatric patients > 1 year in age and as oral formulation in adult and pediatric patients > 6 years old and weight > 16 kg for treatment of invasive aspergillosis and invasive mucormycosis. In the present analysis, an isavuconazole physiologically-based pharmacokinetic (PBPK) model was built and verified in adult and pediatric populations using the Simcyp® simulator. The verified pediatric model was then used to predict the magnitude of DDI risk in pediatric population vs the adult population. The simulations conducted were designed to match the observed clinical trials conducted in adults but with pediatric equivalent doses based on clinical guidelines. Based on the results of the analysis, isavuconazole DDI risk was similar between pediatric and adult populations. When the isavuconazole perpetrator DDI simulations were compared to adults, there was a trend of larger geometric mean (GM) AUC _inf and C _max ratios in patients 1 to < 3 years old. The GM AUC _inf ratio in the 1 to < 3-year-old population ranged from 7 to 36% larger than predicted in the adult population. Based on the results of this analysis and literature reports, it is advisable to show greater caution when considering potential DDI in patients < 3-year-old. In addition, caution should be used in patients < 3 years-old when considering coadministration of isavuconazole with narrow therapeutic index medications such as digoxin and warfarin or medications with large variability in oral bioavailability such as midazolam.