TABLE 1.
Physicochemical and pharmacokinetic parameter input for PBPK model of milademetan
| Parameters (units) | Definition | Values | Data source |
|---|---|---|---|
| Physicochemical properties | |||
| MW (g/mol) | Molecular weight | 618.5 | Calculated |
| logP | Octanol‐to‐water partition coefficient | 3.7 | Predicted by PCModels CLOGP V.4.83 (MOLSIS Inc) |
| pKa | Ionization coefficient | 1.91, 2.26 | Predicted by Pallas UNIX V.4.1.1 (CompuDrug Ltd.) |
| f u,plasma | Plasma protein unbound fraction | 0.02 | Experimental data measured in vitro |
| B/P | Blood‐to‐plasma ratio | 0.784 | Predicted |
| Absorption (ADAM model) | |||
| f u,gut | Unbound fraction in gut enterocyte | 0.02 | Assumed to be equal to fu,plasma |
| Peff,man (10−4 cm/s) | Effective permeability | 1.891 | Predicted based on permeability measured in Caco−2 cell |
| Permeability assay | Caco‐2 | ||
| Apical:basolateral pH | 7.4:7.4 | ||
| Activity | Passive | ||
| PappaA:B (10−6 cm/s) | Apparent permeability | 17 | |
| Reference compound | Propranolol | ||
| Reference compound PappaA:B (10−6 cm/s) | 43 | ||
| Scalar | 1 | Assumed | |
| Transporter | ABCB1 (P‐gp/MDR1) | Exploratory data | |
| Jmax (pmol/min/cm2) | Maximal efflux rate | 13.4 | Calculated from in vitro Caco‐2 transport assay |
| K m (µM) | Michaelis‐Menten constant | 0.324 | Calculated from in vitro Caco‐2 transport assay |
| Distribution (minimal PBPK model) | |||
| V ss (L/kg) | Volume of distribution at steady‐state | 1.8 | Optimized by fitting clinical data (U107) for milademetan alone under fasted conditions |
| k in (1/h) | First‐order rate constant for distribution to the single adjusting compartment | 0.07 | Optimized by fitting clinical data (U107) for milademetan alone under fasted conditions |
| k out (1/h) | First‐order rate constant for distribution from the single adjusting compartment | 0.07 | Optimized by fitting clinical data (U107) for milademetan alone under fasted conditions |
| V sac (L/kg) | Volume of single adjusting compartment | 0.5 | Optimized by fitting clinical data (U107) for milademetan alone under fasted conditions |
| Elimination | |||
| CLint,CYP3A4 (µL/min/pmol of isoform) | CYP3A4‐specific intrinsic clearance | 0.459 | Optimized by fitting clinical data (U107) for milademetan and itraconazole sequence |
| CLint (HLM) (µL/min/mg protein) | Additional hepatic microsomal intrinsic clearance | 40.2 | Optimized by fitting clinical data (U107) for milademetan and itraconazole sequence |
| CLR | Renal clearance | 0 | Assumed |
| CLRbile | Bile clearance | 0 | Assumed |
| Interaction with CYP3A4 | |||
| K i (µM) | CYP3A4 reversible inhibition constant | 4.2 | Experimental data |
| K app (µM) | Apparent inactivation constant for CYP3A4 time‐dependent inhibition | 60.5 | Experimental data |
| K inact (h−1) | Maximal rate constant for enzyme inactivation | 3.71 | Experimental data |
Abbreviations: ADAM, advanced dissolution, absorption, and metabolism; PBPK, physiologically‐based pharmacokinetic.