Risdiplam (Evrysdi) improves motor neuron function in patients with spinal 
muscular atrophy (SMA) and has been approved for the treatment of patients 
≥2 months old. Risdiplam exhibits time-dependent inhibition of cytochrome P450 
(CYP) 3A in vitro. While many pediatric patients receive risdiplam, a drug-drug 
interaction (DDI) study in pediatric patients with SMA was not feasible. 
Therefore, a novel physiologically-based pharmacokinetic (PBPK) model-based 
strategy was proposed to extrapolate DDI risk from healthy adults to children 
with SMA in an iterative manner. A clinical DDI study was performed in healthy 
adults at relevant risdiplam exposures observed in children. Risdiplam caused an 
1.11-fold increase in the ratio of midazolam area under the curve with and 
without risdiplam (AUCR)), suggesting an 18-fold lower in vivo CYP3A 
inactivation constant compared with the in vitro value. A pediatric PBPK model 
for risdiplam was validated with independent data and combined with a validated 
midazolam pediatric PBPK model to extrapolate DDI from adults to pediatric 
patients with SMA. The impact of selected intestinal and hepatic CYP3A 
ontogenies on the DDI susceptibility in children relative to adults was 
investigated. The PBPK analysis suggests that primary CYP3A inhibition by 
risdiplam occurs in the intestine rather than the liver. The PBPK-predicted 
risdiplam CYP3A inhibition risk in pediatric patients with SMA aged 
2 months-18 years was negligible (midazolam AUCR of 1.09-1.18) and included in 
the US prescribing information of risdiplam. Comprehensive evaluation of the 
sensitivity of predicted CYP3A DDI on selected intestinal and hepatic CYP3A 
ontogeny functions, together with PBPK model-based strategy proposed here, aim 
to guide and facilitate DDI extrapolations in pediatric populations.