As certain enzymes, specifically CYP3A4, are ontogeny-specific, the unique ‘age redefining feature’ in the Simcyp Pediatric Simulator was used for this program. Everolimus is both a CYP3A4 and P-gp substrate. This feature accounts for the time variance in very young subjects by simulating the aging elements over time (physical growth, non-linear organ development, age factors, blood flows, ontogeny kicking in). In short, Simcyp Pediatric can simulate the combination of changes resulting from both physiology and ontogeny factors as children age.

The final dosing determination required the prediction of the minimum plasma concentrations (Cmin) to stay within 5–15ng/mL for efficacy. By using the age defining feature in Simcyp, the model showed the dose recommendation of 6 mg/m2 is expected to be effective over the target range of 6 months to 2 years in both the short term (12 weeks of exposure) and long term (up to 2 years of exposure).

TSC is a rare genetic disorder resulting in benign tumours in various organs, including the brain, eyes, heart, kidney, skin, and lungs. The majority of patients with TSC develop epilepsy, and approximately two-thirds become refractory to antiepileptic drugs (AEDs).

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