Pharmacokinetics of therapies approved for spinal muscular atrophy: A narrative review of current evidence

Spinal muscular atrophy is a severe neuromuscular disorder caused by mutations in the survival motor neuron 1 gene, leading to progressive motor neuron degeneration. Over the past decade, disease-modifying therapies targeting the survival motor neuron pathway—nusinersen, onasemnogene abeparvovec, and risdiplam—have significantly transformed the clinical landscape of spinal muscular atrophy. Despite their common therapeutic goal of restoring functional survival motor neuron protein levels, these agents differ markedly in their molecular design, route of administration, pharmacokinetic behavior, and population-specific efficacy. This narrative review provides a comprehensive synthesis of pre- and post-approval pharmacokinetic data from pivotal trials, real-world studies, and population-based modeling. Nusinersen, an intrathecal antisense oligonucleotide, demonstrates prolonged cerebrospinal fluid exposure and slow systemic clearance. Onasemnogene abeparvovec, a single-dose gene therapy, shows sustained survival motor neuron expression mediated by adeno-associated virus 9 vector delivery and episomal persistence in nondividing neurons. Risdiplam, an orally administered survival motor neuron 2 splicing modifier, exhibits systemic bioavailability with reliable central nervous system penetration and predictable pharmacokinetics across age groups. Elimination of gene products and oligonucleotides is a multifaceted process involving enzymatic degradation, immune responses, and excretion through the kidneys or liver. We further discussed how interindividual variability, age, survival motor neuron 2 copy number, and immunological factors influence pharmacokinetic–pharmacodynamic relationships. Personalized treatment strategies for spinal muscular atrophy are increasingly being guided by advances in pharmacokinetic modeling. As the field evolves, biomarker-based monitoring and combination therapies are emerging as promising complementary approaches. With growing clinical experience and an expanding body of pharmacokinetic research on targeted therapies, there is strong potential to further refine treatment strategies—ultimately making spinal muscular atrophy care more effective, safer, and more accessible for patients worldwide.