TABLE 3.
Model parameter estimates of the final phase 3 parent–metabolite enterohepatic circulation model, showing parameter estimates and precision
| Parameter | Value | SE | RSE % | L95% CI | U95% CI |
|---|---|---|---|---|---|
| Fixed effects | |||||
| k a, h−1 | 0.482 | Fixed | ‐ | ‐ | ‐ |
| FRM2 | −0.355 | Fixed | ‐ | ‐ | ‐ |
| CLP/(1‐FRM2), L h−1 | 3.05 | Fixed | ‐ | ‐ | ‐ |
| Sex on regorafenib clearance | 0.169 | Fixed | ‐ | ‐ | ‐ |
| BMI on regorafenib clearance | −0.363 | Fixed | ‐ | ‐ | ‐ |
| VCP/(1‐FRM2), L | 10.7 | Fixed | ‐ | ‐ | ‐ |
| k GE, h−1 | 100 | Fixed | ‐ | ‐ | ‐ |
| Breakfast, h | 08:00 | Fixed | ‐ | ‐ | ‐ |
| Lunch, h | 12:00 | Fixed | ‐ | ‐ | ‐ |
| Dinner, h | 18:00 | Fixed | ‐ | ‐ | ‐ |
| QP/(1‐FRM2), L/h−1 | 11.0 | Fixed | ‐ | ‐ | ‐ |
| VPP/(1‐FRM2), L | 162 | Fixed | ‐ | ‐ | ‐ |
| k CG, h−1 | 0.141 | Fixed | ‐ | ‐ | ‐ |
| DGE, h | 0.5 | Fixed | ‐ | ‐ | ‐ |
| CLM‐2, L h−1 | 1.99 | 0.00508 | 0.255 | 1.98 | 2.00 |
| Sex on M‐2 clearance | 0.380 | 0.0192 | 5.06 | 0.342 | 0.418 |
| CLM‐5, L h−1 | 1.42 | 0.0532 | 3.76 | 1.31 | 1.52 |
| Sex on M‐5 clearance | 0.761 | 0.0387 | 5.08 | 0.685 | 0.837 |
| FRM5 | −1.09 | Fixed | ‐ | ‐ | ‐ |
| Factor IIV CLM‐5 | 2.21 | 0.0752 | 3.41 | 2.06 | 2.35 |
| Individual random effects | |||||
| ω2 k a | 0.127 | Fixed | ‐ | ‐ | ‐ |
| ω2CLP | 0.189 | 0.0123 | 6.53 | 0.165 | 0.213 |
| ω2CLM‐2 | 0.385 | 0.0219 | 5.68 | 0.342 | 0.428 |
| ω2FRM2 | 0.156 | Fixed | ‐ | ‐ | ‐ |
| ω2FRM5 | 0.841 | Fixed | ‐ | ‐ | ‐ |
| ω CLP, CLM‐2/M‐5 | 0.206 | 0.0168 | 8.16 | 0.173 | 0.238 |
| Residual error | |||||
| Parent Prop. error, SD | 0.543 | 0.00124 | 0.229 | 0.540 | 0.545 |
| M‐2 Add. error, SD | 0.001 | Fixed | ‐ | ‐ | ‐ |
| M‐2 Prop. error, SD | 0.485 | 0.00938 | 1.93 | 0.467 | 0.504 |
| M‐5 Add. error, SD | 0.001 | Fixed | ‐ | ‐ | ‐ |
| M‐5 Prop. error, SD | 1.14 | 0.113 | 9.93 | 0.919 | 1.36 |
FRM2 and FRM5 on logit scale corresponds with 41% and 25%, respectively. The estimated factor for IIV on CLM‐5 corresponds with a variance of 0.385.(2.212) = 1.88.
Volumes, clearances and intercompartmental flow are relative to oral bioavailability (Foral), which is not listed for clarity.
Add., additive; BMI, body mass index; CG, central compartment to gallbladder; CI, confidence interval; CL, apparent total body clearance; DGE, duration of gallbladder emptying; FRM2/5, fraction of formation of metabolite M‐2/M‐5; GE, gallbladder emptying; k, rate constant; k a, absorption rate constant; L, lower; P, parent (e.g. in CLP); Prop., proportional; Q, intercompartmental clearance; RSE, relative standard error; SD, standard deviation; SE, standard error; U, upper; VC, central compartment volume; VP, peripheral compartment volume.