TABLE 2

Simulated trials

Type of SimulationTrial and DescriptionDose and Regimen of SonidegibDose and Regimen of Perpetrator
Model development
Study A2114 (internal data): relative bioavailability study and effect of food on sonidegib PK in healthy subjects200 and 800 mg single doses of clinical service form capsule formulation (fasted)NA
Study A2110 (Zollinger et al., 2014): human radiolabeled ADME study in healthy subjects800 mg single doseNA
Study X2101 (Rodon et al., 2014): a phase I, multicenter, open-label, first-in-human, dose-escalation study of sonidegib in patients with advanced solid tumors200 and 800 mg single and multiple q.d. dosesNA
Model verification
Effect of KTZ or RIF on sonidegib PK in healthy subjects (Study A2108)800 mg single dose on day 5KTZ (200 mg b.i.d.) or RIF (600 mg q.d.) days 1–14
Model application
1. Effect of KTZ on sonidegib PK in cancer patientsa. 200 or 800 mg single dose on day 5a. KTZ (200 mg b.i.d.) days 1–14
b. 200 mg q.d. days 1–120b. KTZ (200 mg b.i.d.) days 1–120
c. 200 mg q.d. days 1–133c. KTZ (200 mg b.i.d.) days 120–133 (14 days)
d. 200 mg q.o.d. days 1–133d. KTZ (200 mg b.i.d.) days 120–133 (14 days)
e. 200 mg q.d. days 1–28, 200 mg q.o.d. days 29–42, 200 mg q.d. days 43–112ae. KTZ (200 mg b.i.d.) days 29–42
2. Effect of RIF on sonidegib PK in cancer patientsa. 200 or 800 mg single dose on day 5a. RIF (600 mg q.d.) days 1–14
b. 200 mg q.d. days 1–120b. RIF (600 mg q.d.) days 1–120
c. 200 mg q.d. days 1–133c. RIF (600 mg q.d.) days 120–133 (14 days)
d. 200 mg q.d. days 1–28, 800 mg q.d. days 29–42, 200 mg q.d. days 43–112a,bd. KTZ (200 mg b.i.d.) days 29–42
3. Effect of ERY on sonidegib PK in cancer patientsa. 200 mg single dose on day 5a. ERY (500 mg q.i.d.) days 1–14
b. 200 mg q.d. days 1–120b. ERY (500 mg q.i.d.) days 1–120
c. 200 mg q.d. days 1–133c. ERY (500 mg q.i.d.) days 120–133 (14 days)
4. Effect of EFV on sonidegib PK in cancer patientsa. 200 mg single dose on day 5a. EFV (600 mg q.d.) days 1–14
b. 200 mg q.d. days 1–120b. EFV (600 mg q.d.) days 1–120
c. 200 mg q.d. days 1–133c. EFV (600 mg q.d.) days 120–133 (14 days)
  • NA, not applicable.

  • a PK assessed on day 43 (0–24 hours).

  • b Due to a technical limitation of Simcyp, to simulate the PK of 800 mg (fa = 0.15), the compound file for the 200 mg dose was used and the dose was entered as 400 mg (fa = 0.30) in the custom dosing table. The exposure to 400 mg (with fa = 0.3) was identical to the exposure to 800 mg (with fa = 0.15).