Safety of sirolimus in pediatric vascular anomalies: a BKMR-PopPK exposure-response framework for individualized risk and dosing.

BACKGROUND: Vascular anomalies are rare, heterogeneous disorders that threaten the health of children. Sirolimus is an important drug therapy, but its high incidence of adverse drug reactions (ADRs) may cause treatment discontinuation and therefore poor disease control. Although prior studies suggest a strong link between sirolimus exposure and ADRs, the quantitative relationship remains unclear. This study aimed to systematically quantify the relationships between steady-state trough sirolimus concentrations (Cmin) and three ADRs: myelosuppression, abnormal liver function, and dyslipidemia. METHODS: We retrospectively analyzed the data using Bayesian kernel machine regression (BKMR) to characterize associations of Cmin and its determinants with ADRs, and further developed an integrated BKMR-population pharmacokinetic (PopPK) framework for quantitative risk assessment and prediction. RESULTS: A total of 257 patients were involved in this study (766-892 blood samples). BKMR results showed the quantitative exposure-response relationships between Cmin and ADRs, identifying disease complexity and duration of treatment as key risk modifiers. We recommend routine Cmin monitoring within safety windows: 5.0-7.5 ng/mL for simple lesions or milder disease; 8.0-10.2 ng/mL for complex or mixed vascular malformations. Stricter ADR surveillance is warranted in complex malformations, and during long-term therapy (> 6 months), vigilance for myelosuppression and dyslipidemia through regular screening is also warranted. CONCLUSIONS: This is the first study to quantify the relationship between Cmin and ADRs in pediatric vascular anomalies. The integrated BKMR-PopPK framework provides a tool for translating pharmacological insights into practice and advancing model-informed precision dosing (MIPD). These findings support therapeutic drug monitoring (TDM)-based target ranges, addressing a knowledge gap and reducing reliance on empirical dosing. This paradigm also informs safety evaluation and early-phase trials in other pediatric rare diseases with limited samples.