Table 1.
Input Parameters Used to Simulate the Kinetics of Selumetinib
| Parameter | Value | Reference |
|---|---|---|
| MW | 457.7 | Internal database |
| logP | 3.88 | Internal database |
| Compound type | Diprotic base | Internal database |
| pKa | 8.2, 2.7 | Internal database |
| B:P | 0.625 | 0.556‐0.714, Report KPJ003 |
| fu | 0.016 | Report KPJ003 |
| MDCK II, 10–6 cm/s | 37.7 | Report KMN036 |
| Peff,man , ×10–4 cm/s | 4.82 | Predicted |
| Q, L/h | 8 | Population PK model predicted |
| Vss, L/kg | 1.37 | Predicted (Method 2: after Rodgers and Rowland 17 ) |
| Vsac, L/kg | 1 | Estimated based on observed Cmax and PK profile (Study NCT02093728) |
| CYP3A CLint, μL/min/pmol | 0.568 | Retrograde: CLpo = 19.6 L/h (pooled CL/F from 9 studies), fm = 25% |
| CYP2C19 CLint, μL/min/pmol | 3.335 | Retrograde: CLpo = 19.6 L/h (pooled CL/F from 9 studies), fm = 15% |
| Additional liver HLM, μL/min/mg | 186.8 | Retrograde: CLpo = 19.6 L/h (pooled CL/F from 9 studies) |
B:P, blood‐to‐plasma ratio; CL/F, clearance/bioavailability = oral clearance; CLint, intrinsic clearance; CLpo, oral clearance; Cmax, maximum plasma concentration; fm, fraction metabolized; fu, unbound fraction in plasma; HLM, human liver microsome; logP, partition coefficient; MDCK, Madin‐Darby Canine Kidney; MW, molecular weight; Peff,man , human intestinal effective permeability; PK, pharmacokinetic; pKa, acid dissociation constant (logarithmic scale); Q, intercompartmental clearance; Vsac, volume of single adjusting compartment; Vss, volume of distribution at steady state.