Pharmacovigilance and network toxicology analysis of risdiplam-associated adverse events in pediatric patients with spinal muscular atrophy.

Abstract

Risdiplam, a survival motor neuron 2 (SMN2) splicing modifier for pediatric spinal muscular atrophy (SMA), requires a comprehensive real-world safety evaluation. This study analyzed 1059 pediatric adverse event reports from the FDA Adverse Event Reporting System (2020 Q1-2025 Q4) with risdiplam as the primary suspect drug. Female patients slightly predominated, with 50.9% aged 0-5 years. Disproportionality analyses identified 25 positive signals. Infections and infestations, general disorders, and gastrointestinal disorders were most frequent. Pneumonia, pyrexia, diarrhoea, respiratory tract infection, and nasopharyngitis were most commonly reported. Notably, nephrolithiasis emerged as a novel unlabeled signal in pediatric patients (reporting odds ratio = 11.32). Median time-to-onset was 119 days, with approximately one-third of events occurring within 30 days and another one-third after 1 year. The Weibull model revealed that the top 5 most frequently reported PTs and top 5 SOCs all exhibited an early-onset pattern. Network toxicology identified 75 overlapping targets, with CASP3, HDAC1, and PDGFRA as core targets implicated in calcium signaling, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt), and apoptosis pathways. Molecular docking confirmed stable binding (- 10.1 to - 8.6 kcal/mol). Risdiplam demonstrates a generally acceptable long-term safety profile in clinical practice, yet vigilant monitoring of respiratory, infectious, gastrointestinal, and renal adverse events remains essential to optimize the benefit-risk balance.