Figure 2.

Comparisons of simulated risdiplam and midazolam pharmacokinetics by the PBPK model with the observed data in adults and pediatric population. (a) Risdiplam plasma concentration‐time profiles after oral 8 mg once daily administration for 14 days in 27 healthy subjects. The plot in semi‐log scale as well as the profiles after 5 mg are shown in Supplementary Material ‐5 . (b) Midazolam plasma concentration‐time profiles after 2 mg oral administration in the presence of risdiplam predicted with the refined k _inact (1/18 of the in vitro k _inact). Sixty percent of the samples at 24 hours after midazolam administration were below the quantification limit (0.1 ng/mL). Observations (circles) and simulations as median (solid line) and 90% prediction interval (shaded area) are shown. Simulated risdiplam (c) C_max and (d) AUC_0–24h values in pediatric patients (gray shade) compared with the observed C_max and individually estimated AUC_0–24h using post hoc PK parameters of population PK model (striped shade). ³⁵ Geometric means of simulated (solid squares) and observed (open circles) values are shown. The observations originate from 372 pediatric patients with SMA aged 2 months–18 years. Geometric means of the simulated risdiplam C_max and AUC_0–24h are within 0.8–1.25 fold of the observations except for C_max of 2–7 months (0.636) and AUC_0–24h of 2–4 years (1.29) and 4–7 years (1.26). AUC_0–24h, area under the concentration‐time curve over 24 hours; C_max, maximum concentration; k _inact, inactivation constant; PBPK, physiologically‐based pharmacokinetic.