Table 3.
Plasma and organ pharmacokinetic parameters of selpercatinib in male wild-type and Abcb1a/1b; Abcg2−/− mice over 2 h after oral administration of 10 mg/kg selpercatinib with or without elacridar.
| Parameter | Genotype/Groups | |||
|---|---|---|---|---|
| Vehicle | Elacridar | |||
| Wild-Type | Abcb1a/1b;Abcg2−/− | Wild-Type | Abcb1a/1b;Abcg2−/− | |
| AUC0–2h, ng/mL*h | 14,092 ± 2816 | 15,098 ± 1503 | 12,928 ± 3121 | 17,294 ± 1513 # |
| Fold change AUC0–2h | 1.0 | 1.1 | 0.92 | 1.2 |
| Cmax, ng/mL | 8739 ± 1560 | 8865 ± 792 | 7466 ± 1848 | 9617 ± 776 # |
| Tmax, h | 0.75 ± 0.27 | 1.0 ± 0.0# | 0.50 ± 0.27 | 0.79 ± 0.33 |
| Cbrain, ng/g | 210 ± 40 | 4726 ± 638 ***### | 2765 ± 851 *** | 4713 ± 484 ***### |
| Fold increase Cbrain | 1.0 | 22.5 | 13.2 | 22.4 |
| Brain-to-plasma ratio | 0.041 ± 0.009 | 0.68 ± 0.18 ***### | 0.46 ± 0.03 *** | 0.54 ± 0.06 *** |
| Fold increase ratio | 1.0 | 17 | 11.5 | 13.5 |
| CLiver, ng/g | 18,134 ± 2604 | 21,445 ± 2330 | 20,028 ± 4435 | 23,628 ± 4827 |
| Fold increase Cliver | 1.0 | 1.2 | 1.1 | 1.3 |
| Liver-to-plasma ratio | 3.5 ± 0.8 | 3.1 ± 0.7 | 3.4 ± 0.3 | 2.7 ± 0.4 |
| Fold change ratio | 1.0 | 0.89 | 1.0 | 0.77 |
| CSI + SIC, ng/g | 37,604 ± 13,607 | 18,845 ± 3628 ** | 26,630 ± 6802 | 21,226 ± 929 * |
| Fold increase CSI + SIC | 1.0 | 0.50 | 0.71 | 0.56 |
| SI + SIC-to-plasma ratio | 7.0 ± 1.9 | 2.7 ± 0.8 ***## | 4.6 ± 1.3 * | 2.4 ± 0.2 ***## |
| Fold change ratio | 1.0 | 0.39 | 0.66 | 0.34 |
| Ctestis, ng/g | 788 ± 159 | 7020 ± 664 *** | 5709 ± 1744 *** | 9202 ± 856 ***### |
| Fold increase Ctestis | 1.0 | 8.9 | 7.2 | 11.7 |
| Testis-to-plasma ratio | 0.15 ± 0.03 | 1.0 ± 0.2 *** | 0.94 ± 0.08 *** | 1.1 ± 0.05 *** |
| Fold change ratio | 1.0 | 6.7 | 6.3 | 7.3 |
Data are given as mean ± S.D. (n = 6). AUC0–2h, area under the plasma concentration–time curve; Cmax, maximum concentration in plasma; Tmax, time point (h) of maximum plasma concentration; Cbrain, brain concentration; Cliver, liver concentration; SI, small intestine (tissue); SIC, small intestine contents; CSI+SIC, small intestine tissue together with small intestine contents concentration; Ctestis, testis concentration; *, p < 0.05; **, p < 0.01; ***, p < 0.001 compared to vehicle-treated wild-type mice; #, p < 0.05; ##, p < 0.01; ###, p < 0.001 compared to elacridar-treated wild-type mice; ^, p < 0.05; ^^, p < 0.01; ^^^, p < 0.001 compared between vehicle-treated Abcb1a/1b;Abcg2−/− and elacridar-treated Abcb1a/1b;Abcg2−/− mice. Statistical analysis was applied after log-transformation of linear data.