Observed and simulated clinical PK parameters of sonidegib in the presence and absence of the strong CYP3A perpetrators, KTZ and RIF, in healthy subjects
| Treatment | Statistics | AUC0–240 (ng × h/ml) | Cmax (ng/ml) | ||
|---|---|---|---|---|---|
| Observed | Simulateda | Observed | Simulated | ||
| 800 mg sonidegib single dose on day 5 | n | 16 | 100 | 16 | 100 |
| Mean (S.D.) | 6080 (2530) | 6431 (2993) PE = +6% | 246 (158) | 238 (73.4) PE = −3% | |
| CV% mean | 41.6 | 46.5 | 64.4 | 30.9 | |
| GM | 5620 | 5816 PE = +3% | 212 | 227 PE = +7% | |
| CV% GM | 42.0 | —b | 56.3 | — | |
| 800 mg sonidegib single dose on day 5 + KTZ (200 mg b.i.d.) days 1–14 | n | 15 | 100 | 15 | 100 |
| Mean (S.D.) | 13,400 (4430) | 15,043 (6638) PE = +12% | 330 (102) | 351 (102) PE = +6% | |
| CV% mean | 33.0 | 44.1 | 30.8 | 29.0 | |
| GM | 12,700 | 13,778 PE = +8% | 316 | 337 PE = +7% | |
| CV% GM | 38.2 | — | 31.9 | — | |
| GM ratio (CI) | 2.25 (1.78, 2.86) | 2.37 (2.25, 2.49) PE = +5% | 1.49 (1.11, 1.99) | 1.48 (1.44, 1.52) PE = −1% | |
| 800 mg sonidegib single dose on day 5 + RIF (600 mg q.d.) days 1–14 | n | 16 | 100 | 16 | 100 |
| Mean (S.D.) | 1660 (579) | 1172 (851) PE = −29% | 111 (54.5) | 90.8 (49.2) PE = -18% | |
| CV% mean | 34.8 | 72.6 | 49.0 | 54.2 | |
| GM | 1550 | 912 PE = -41% | 97.7 | 78.4 PE = −20% | |
| CV% GM | 41.6 | — | 60.5 | — | |
| GM ratio (CI) | 0.276 (0.219, 0.349) | 0.157 (0.141, 0.175) PE = −43% | 0.461 (0.346, 0.613) | 0.346 (0.319, 0.375) PE = −25% | |
CI, confidence interval (90%); n, number of subjects with nonmissing values; PE, prediction error % = [(predicted value − observed value)/observed value] × 100.
↵a Simulated data for control arm is reported from the sonidegib and KTZ simulation. There was little difference in the PK parameters observed in the control arm of the sonidegib and RIF simulation compared with the control arm of the sonidegib and KTZ simulation.
↵b Not available.