Methodological considerations on paracetamol pharmacokinetics in spinal muscular atrophy: A response to Zhao et al.

We have reviewed with great interest the recent study examining the pharmacokinetics (PK) of paracetamol in patients with spinal muscular atrophy (SMA).1 Paracetamol remains a critical antipyretic and analgesic agent for patients with SMA, who are prone to frequent pain and pyrexia due to recurrent infections, immobility and disease-related complications. While the authors provide valuable preliminary insights into dosing challenges in this rare population, several methodological and interpretative limitations warrant discussion to contextualize the findings.1 At the start, the small sample size (n = 12 patients with SMA, of whom 6 children/6 adults vs. 11 healthy controls) restricts covariate analysis, as both statistical power and adequate variability in covariates are prerequisites for robust population PK modelling. For instance, narrow weight ranges may obscure the true weight–PK relationships, despite the inclusion of larger cohorts. While the rarity of SMA complicates recruitment, the combined paediatric-adult analysis risks masking age-specific PK determinants, considering the developmental changes in body composition and organ function.2, 3 We acknowledge that Zhao et al. recognized this limitation in their discussion and attempted to mitigate age-related variability through allometric scaling of body weight. While this approach improves model generalizability across size differences, it may not fully account for maturational physiological differences in this patient cohort, which may influence drug clearance independently of body size leading to clinically relevant differences.