Table 2.
Physiologically based pharmacokinetic model-predicted effects of osilodrostat on cytochrome P450 (CYP) substrates after single (50-mg) or multiple (30-mg twice-daily) doses of osilodrostat
| Probe substrate | Treatmenta | Predicted geometric mean ratio (prediction error, %)b | |
|---|---|---|---|
| AUClast (48 h) | C max | ||
| Caffeine (CYP1A2) | Single dose (osilodrostat 50 mg) | 1.66 (−29%) | 1.17 (+9.3%) |
| Multiple dose (osilodrostat 30 mg twice daily) | 1.67 | 1.15 | |
| Omeprazole (CYP2C19) | Single dose (osilodrostat 50 mg) | 1.55 (−19%) | 1.44 (−11%) |
| Multiple dose (osilodrostat 30 mg twice daily) | 1.95 | 1.73 | |
| Dextromethorphan (CYP2D6) | Single dose (osilodrostat 50 mg) | 1.47 (−0.7%) | 1.43 (+5.9%) |
| Multiple dose (osilodrostat 30 mg twice daily) | 1.52 | 1.47 | |
| Midazolam (CYP3A4/5) | Single dose (osilodrostat 50 mg) | 1.49 (−0.67%) | 1.39 (−5.4%) |
| Multiple dose (osilodrostat 30 mg twice daily) | 1.51 | 1.45 | |
AUC last (48 h) area under the concentration-time curve from time zero to the last measureable concentration at 48 h, C max maximum plasma concentration
aSimulated single dose of osilodrostat 50 mg plus substrate on day 1 or predicted multiple doses of osilodrostat 30 mg twice daily on days 1–16 plus a single dose of substrate on day 14
bCalculated prediction error (%) = [(predicted value − observed value)/observed value] × 100; observed values are shown in Fig. 2