Table 2.
Parameters values used for the EVR PBPK simulations
| EVR | Values | Reference/Comments |
|---|---|---|
| Dose (mg) | 10 | Ref.16 |
| Chemical Structure |  |
|
| Physicochemical properties | ||
| MW (g/mol) | 958.22 | Ref.81 |
| Log PO:W | 4.23 | Calculated using ACD software40 |
| Compound type | Neutral | Ref.82 |
| Blood-to-plasma ratio (Cb/Cp) | 3.4 at 5 ng/ml | Ref.38, see text for details |
| 4.55 at 50 ng/ml | ||
| 4.58 at 100 ng/ml | ||
| 1.9 at 500 ng/ml | ||
| 1.1 at 1 µg/ml | ||
| 0.71 at 5 µg/ml | ||
| Hematocrit value (%) | 45 | Simcyp default value |
| fu | 0.26 | Ref.42 |
| Absorption [Advanced dissolution, absorption and metabolism (ADAM) model] | ||
| fu,gut | 1 | Assumed value |
| Peff,man (x10−4 cm/s) | 6.67 | Predicted using the Simcyp mechanistic Peff (MechPeff) model Jejunum 1 regional permeability using logP input |
| Distribution (minimal PBPK with single adjusting compartment) | ||
| Vss (L/kg) | 1.55 (CV 36.0%) | Ref.83 |
| Vsac (L/kg) | 1.529 | Optimised in Simcyp Simulator |
| kin (1/h) | 0.493 | Optimised Ref.41 |
| kout (1/h) | 0.0993 | Optimised Ref.41 |
| Kp,liver | 1 | Default value |
| Elimination | ||
| CL/F (L/h) | 15.4 (CV 34.3%) | Ref.38 |
| CLR (L/h) | 0 | Ref.45 |
| Transport | ||
| Intestinal efflux intrinsic clearance | ||
| CLint,T,P-gp (µL/min) | 7 | Optimised for 10 mg daily dose at steady state47 and 10 mg weekly dose38, verified against 10 mg steady-state dose in an independent study Ref.49 |
| Interaction | ||
| Ki,OATP1B1 (µM) | 0.022 | Calibrated by CsA |
| Ki,OATP1B3 (µM) | 0.044 | Calibrated by CsA |
| CYP3A4 | ||
| Ki (µM) | 0.09 | Ref.47 |
| fu,mic | 0.14 | |
| CYP3A5 | ||
| Ki (µM) | 0.09 | Ref.47 |
| fu,mic | 0.14 | |
Po:w: neutral species octanol:buffer partition coefficient
fu,gut: unbound fraction of drug in enterocytes
Peff,man: human jejunum effective permeability
Vss: volume of distribution at steady state
Vsac: volume of distribution of single adjusting compartment
Kp,liver: liver-plasma concentration ratio