Table 2.
Plasma and organ pharmacokinetic parameters of selpercatinib in male wild-type, Abcb1a/1b -/-, Abcg2-/- and Abcb1a/1b; Abcg2-/- mice over 4 h after oral administration of 10 mg/kg selpercatinib.
| Parameter | Genotype | |||
|---|---|---|---|---|
| Wild-Type | Abcb1a/1b-/- | Abcg2-/- | Abcb1a/1b;Abcg2-/- | |
| AUC0–4h, ng/mL*h | 23,670 ± 2469 | 37,024 ± 9634 ** | 39,056 ± 6710 *** | 38,986 ± 4711 *** |
| Fold change AUC0–4h | 1.0 | 1.6 | 1.7 | 1.6 |
| Cmax, ng/mL | 6908 ± 761 | 10,338 ± 2641 ** | 11,447 ± 2155 *** | 11,015 ± 1653 ** |
| Tmax, h | 1.6 ± 1.4 | 1.8 ± 1.3 | 1.4 ± 0.74 | 1.5 ± 1.3 |
| Cbrain, ng/g | 420 ± 66 | 1998 ± 233 ***### | 418 ± 102 ### | 4263 ± 853 *** |
| Fold change Cbrain | 1.0 | 4.8 | 1.0 | 10.2 |
| Brain-to-plasma ratio | 0.077 ± 0.018 | 0.23 ± 0.04 ***### | 0.052 ± 0.011 *### | 0.48 ± 0.07 *** |
| Fold change ratio | 1.0 | 3.0 | 0.68 | 6.2 |
| CLiver, ng/g | 25,737 ± 3219 | 34,014 ± 7169 ## | 19,334 ± 3483 * | 23,157 ± 3900 |
| Fold increase Cliver | 1.0 | 1.3 | 0.75 | 0.90 |
| Liver-to-plasma ratio | 4.7 ± 0.7 | 3.9 ± 1.0 # | 2.4 ± 0.3 *** | 2.6 ± 0.5 *** |
| Fold change ratio | 1.0 | 0.83 | 0.51 | 0.55 |
| CSI, ng/g | 21,649 ± 26,731 | 16,952 ± 2729 | 12,967 ± 3639 | 11,576 ± 734 |
| Fold increase CSI | 1.0 | 0.83 | 0.60 | 0.53 |
| SI-to-plasma ratio | 3.7 ± 4.3 | 2.0 ± 0.6 | 1.6 ± 0.4 | 1.3 ± 0.1 |
| Fold change ratio | 1.0 | 0.54 | 0.43 | 0.35 |
| CSIC, ng/g | 98,083 ± 38,906 | 69,396 ± 15,655 ## | 91,686 ± 35,700 ### | 27,386 ± 3533 *** |
| Fold increase CSIC | 1.0 | 0.71 | 0.93 | 0.28 |
| SIC-to-plasma ratio | 18.2 ± 8.5 | 8.1 ± 2.9 *## | 11.4 ± 3.9 ### | 3.1 ± 0.68 *** |
| Fold change ratio | 1.0 | 0.45 | 0.63 | 0.17 |
| SIC percentage of dose, % | 2.3 ± 0.9 | 1.1 ± 0.3 | 1.6 ± 0.7 # | 0.69 ± 0.52 *** |
| Fold change ratio | 1.0 | 0.48 | 0.70 | 0.30 |
| Ctestis, ng/g | 810.8 ± 148.4 | 3477 ± 634.1 ***### | 1049 ± 192.2 ### | 8328 ± 934.8 *** |
| Fold change Ctestis | 1.0 | 4.3 | 1.3 | 10.3 |
| Testis-to-plasma ratio | 0.15 ± 0.02 | 0.39 ± 0.06 ***### | 0.13 ± 0.03 ### | 0.94 ± 0.10 *** |
| Fold change ratio | 1.0 | 2.7 | 0.90 | 6.4 |
Data are given as mean ± S.D. (n = 6). AUC0–4h, 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); CSI, small intestine tissue concentration; SIC, small intestine contents; CSIC, small intestine contents concentration; Ctestis, testis concentration; *, p < 0.05; **, p < 0.01; ***, p < 0.001 compared to wild-type mice; #, p < 0.05; ##, p < 0.01; ###, p < 0.001 compared to Abcb1a/1b;Abcg2-/- mice. Statistical analysis was applied after log-transformation of linear data.