Table 1 The used PBPK modelling parameters for ROF and ROF N-oxide

MW(g·mol⁻¹)

403.21

419.21

Chemspider

pKa (Base)

13.3 (acid); 2.4 (base)

12.92, 0.65

[9], Optimized for ROF N-oxide

LogP

3.5

2.6

Optimized

Solubility (μg·mL⁻¹)

0.5 (@pH7.4)

-

[9]

P_app (X 10^–5 cm⋅s⁻¹)

0.01

-

[20]

f_up

0.011

0.034

[9]

R_bp

0.73

0.62

Calculated by PK-Sim

CYP3A4 CL_int,u (μL/min/mg)^a

0.90/0.55

0.010/0.0093

Optimized based on the observed human PK

CYP1A2 CL_int,u (μL/min/mg)^a

0.55/0.33

-

Calculated based on lower clearance in COPD patients

CL_a (μL/min/mg)^a

-

0.10/0.093

CL_R(L/h)

GFR*f_up

Default

GFR fraction

1.0

Default

K_Ins,p scale

5.0

-

Optimized based on the observed human PK

Partition coefficients

Rodgers and Rowland

Optimized based on the observed human PK

Cellular permeabilities

PK-Sim Standard

Concentration (μM/L liver tissue)

 CYP3A4

4.32

Default

 CYP1A2

1.80

Abundance in HLM (pmol/mg protein)

 CYP3A4

137

[21]

 CYP1A2

52

k_deg

 CYP3A4

0.019 h⁻¹(liver),0.03 h⁻¹ (intestine)

[22]

 CYP1A2

0.017 h⁻¹(liver), 0.03 h⁻¹ (intestine)

K_i CYP3A4 (μM)

2.79

-

[9]