Input parameters of risdiplam PBPK model
| Parameter | Value | Sources |
|---|---|---|
| Molecular weight | 401.5 g/mol | |
| Compound type | Diprotic base pKa1 = 4.52 pKa2 = 6.82 | Measured |
| LogD* | 2.51 (pH = 7.4) | Measured |
| Permeability (Peff) | 20.4 ×10−6 cm/s | Measured |
| B:P ratio | 1.3 | Measured |
| Protein binding | 89% | Measured |
| Absorption | ||
| FA | >0.9 | Predicted by ADAM model |
| fu,gut | 1 | (Yang et al., 2007) |
| Distribution | 4.1 l/kg | Full PBPK model with predicted Kp values (Rodgers and Rowland, 2006) |
| Metabolism | ||
| CLint,CYP3A4 (µl/min/pmol) | 0.018 | According to itraconazole DDI study results (Sturm et al., 2019) |
| CLint,FMO3 (µl/min/pmol) | 0.364 | Calculated based on in vitro and clinical study results |
| Elimination | ||
| CLR (l/h) | 0.33 | According to the observations in healthy individuals (Sturm et al., 2019) |
*The corresponding LogP is 2.61.
ADAM, advanced dissolution, absorption, and metabolism; B:P, blood to plasma; CLint, intrinsic clearance; CLR, renal clearance; DDI, drug-drug interaction; FA, fraction absorbed; fu,gut, unbound fraction in enterocyte; Kp, tissue-plasma partition coefficient; PBPK, physiologically based pharmacokinetic; Peff, effective permeability.