Physiologically Based Pharmacokinetic Modeling of Venetoclax in Pediatric Acute Myeloid Leukemia: Food Effects, Age-Related Pharmacokinetics, and Voriconazole-Mediated Drug–Drug Interactions

Background: Venetoclax (VEN), a selective B-cell lymphoma 2 inhibitor, has been increasingly used off-label in pediatric patients with hematologic malignancies. However, its pharmacokinetic characteristics in pediatric patients remain insufficiently characterized. Methods: An adult VEN physiologically based pharmacokinetic (PBPK) model was developed and extrapolated to children using age-dependent physiological and CYP3A4 ontogeny data. The pediatric model was calibrated and evaluated using data from 76 children with AML (203 plasma concentrations) and subsequently applied to assess food effects, age-related pharmacokinetic differences, and VEN dose-reduction scenarios during VCZ co-administration. The clinical study was registered with the Chinese Clinical Trial Registry (ChiCTR1900027146 and ChiCTR2400080307). Results: The adult and pediatric models adequately reproduced the observed VEN concentration–time profiles. At 200 mg/m2, a normal-fat meal increased predicted AUCinf and Cmax by 2.74- and 1.77-fold, respectively, versus a low-fat meal. Children aged 2–<6 years had the highest exposure; AUCinf was 1.44- and 1.91-fold higher than in the 6–<12- and 12–<18-year groups, respectively. During VCZ co-administration, reducing VEN to 50% and 25% of the full dose decreased AUC0–168h by 36.8% and 60.5% and Cmax by 42.5% and 70.5%, respectively, with minimal changes in Tmax. Conclusions: The pediatric VEN PBPK model quantitatively characterized the effects of meal conditions, developmental age, and VCZ-mediated CYP3A inhibition on VEN pharmacokinetics. These findings support administration with a normal diet, closer safety monitoring in children aged 2–<6 years receiving 200 mg/m2, and model-informed evaluation of VEN dose reduction during concomitant VCZ therapy.