TABLE 2.
Summary of observed and simulated remibrutinib parameters using the established PBPK model
| PK parameters | Observed mean value | Simulated mean value |
|---|---|---|
| CL (L/h) | 70.1 ± 12.8a | 73.1 ± 14.1c |
| Fa (%) | 86.9e | 88.9 ± 9.70 |
| Fg (%) | 78.9 ± 15.6 | 55.4 ± 14.6 |
| Fh (%)d | 49.3d | 62.3 ± 10.7 |
| F (%) | 33.8 ± 11.5 | 30.6 ± 10.1 |
| F inhibited (%)b | 80.9 ± 11.5 | 70.8g |
| fm (CYP3A4) (%) | 40.0 | 43.0 ± 10.8 |
| V ss (Subs) (L/Kg) | 0.81 ± 0.22f | 0.812 ± 0.228 |
After target saturation (third dose 0.1 mg i.v.), due to short t 1/2 no accumulation.
Bioavailability in the presence of ritonavir.
Clearance after target saturation (third dose) in ritonavir DDI study simulation with 20 mg remibrutinib at day 3.
Observed first‐pass metabolism (Fh ) calculated:
Fh = AUCratio,iv/(AUCratio,po * Fg ) where AUCratio of the ritonavir DDI study were used.
Observed Fa calculated: Fa = F/Fg /Fh ).
Observed value, calculated from mean V ss: 63.1 L divided by mean body weight of 77.8 kg.
Calculated based on PBPK simulations: remibrutinib p.o. AUCinhibited divided by i.v. AUCinhibited by ritonavir.
Abbreviations: AUCratio, area under the blood concentration–time; CL, systemic drug clearance; DDI, drug‐drug interaction; F, absolute bioavailability; Fa , fraction of the dose absorbed from gastrointestinal tract; Fg , fraction of the dose escaping intestinal first‐pass metabolism; Fh , fraction of the dose escaping hepatic first‐pass metabolism; F inhibited, absolute bioavailability when inhibiting CYP3A4; fm (CYP3A4), fraction of the drug metabolized via CYP3A4; PBPK, physiologically‐based pharmacokinetic; PK, pharmacokinetic; t 1/2, terminal elimination half‐life; V ss, apparent volume of distribution at steady‐state.