Table 3.
Comparison of clinical study outcomes to physiologically based pharmacokinetic model predictions
| Observed | Predicted (Berkeley Madonna) | Predicted (SimCYP) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Geometric mean (CV%) | Geometric mean | Geometric mean | ||||||||||
| Outcome | Control | Treatment | Treatment/control ratio (90% CI) | P‐value[Link] | Control | Treatment | Treatment/control ratio | Control | Treatment | Treatment/control ratio (90% CI) | ||
| Raloxifene | ||||||||||||
| t1/2 (h) | 32.6 (32) | 30.2 (47) | 0.93 (0.90–1.3) | – | 55.5 | 57.0 | 1.03 | 58.5 (17) | 56.0 (19) | 0.96 (0.94–0.99) | ||
| Cmax (nM) | 0.40 (58) | 0.40 (77) | 0.99 (0.81–1.2) | 0.96 | 0.45 | 0.58 | 1.29 | 0.33 (38) | 0.34 (38) | 1.04 (1.02–1.07) | ||
| AUC0‐inf (nM[Link]h) | 16.3 (63) | 17.9 (75) | 1.09 (0.92–1.3) | 0.35 | 20.7 | 27.9 | 1.31 | 18.6 (40) | 19.6 (41) | 1.05 (1.03–1.08) | ||
| R4G | ||||||||||||
| t1/2 (h) | 15.4 (48) | 16.8 (75) | 1.09 (0.65–1.3) | – | – | – | – | – | – | – | ||
| Cmax (nM) | 106 (61) | 114 (76) | 1.08 (0.75–1.5) | 0.63 | – | – | – | – | – | – | ||
| AUC0‐inf (nM[Link]h) | 1380 (68) | 1290 (66) | 0.93 (0.65–1.3) | 0.58 | – | – | – | – | – | – | ||
| R6G | ||||||||||||
| t1/2 (h) | 15.6 (75) | 15.8 (77) | 1.01 (0.70–1.4) | – | – | – | – | – | – | – | ||
| Cmax (nM) | 15.8 (69) | 14.5 (58) | 0.92 (0.77–1.1) | 0.45 | – | – | – | – | – | – | ||
| AUC0‐inf (nM[Link]h) | 324 (91) | 317 (80) | 0.97 (0.78–1.2) | 0.87 | – | – | – | – | – | – | ||
| Silybin A | ||||||||||||
| Cmax (nM) | – | 319 (118) | – | – | – | 243 | – | – | 252 (53) | – | ||
| t1/2 (h) | – | 1.52 (50) | – | – | – | 6.3 | – | – | 2.8 (48) | – | ||
| Silybin B | ||||||||||||
| Cmax (nM) | – | 210 (136) | – | – | – | 231 | – | – | 218 (40) | – | ||
| t1/2 (h) | – | 1.23 (50) | – | – | – | 5.3 | – | – | 1.7 (48) | – | ||
R4G, raloxifene‐4′‐glucuronide; R6G, raloxifene‐6‐glucuronide; t1/2, terminal elimination half‐life; Cmax, maximal concentration; AUC0‐inf, area under the concentration‐time curve from time zero to infinity.
*Paired two‐tailed Student's t‐test on log‐transformed data (control vs. treatment).