Figure 3.

Predicted AUCR of midazolam in the presence of risdiplam in pediatric patients with SMA aged 2 months–18 years. (a) Extrapolation of the DDI using Upreti and Johnson functions for the hepatic and intestinal CYP3A ontogeny, respectively. The open circles and shaded area show geometric means and 5^th to 95^th percentiles of the predicted midazolam AUCR. The dotted lines indicate the ratios of 1.25 and 2 for weak and moderate inhibition, respectively. (b) Simulations with ranges of ontogeny functions and estimated in vivo k _inact values to cover uncertainty in the physiology and drug‐related parameters of the DDI risk assessments. The 5^th to 95^th percentiles of the predicted AUCR are shown for each scenario. For UGT1A4 of the midazolam model, the steep ontogeny function for UGT1A4 (Supplementary Material ‐9 ) was used. AUCR, ratio of midazolam area under the curve with and without risdiplam; CYP, cytochrome P450; DDI, drug–drug interaction; k _inact, inactivation constant; SMA, spinal muscular atrophy; UGT, uridine 5′‐diphospho‐glucuronosyltransferase.