TABLE 3.
Pharmacokinetic parameters, brain concentrations, and brain‐to‐plasma ratios of larotrectinib in male wild‐type, Cyp3a −/−, and Cyp3aXAV mice over 4 hr after oral administration of 10 mg·kg−1 of larotrectinib
| Parameter | Genotype | ||
|---|---|---|---|
| Wild‐type | Cyp3a −/− | Cyp3aXAV | |
| AUC0–4 hr (ng·ml−1·hr−1) | 1,246 ± 228 | 2,174 ± 286 * | 614 ± 192 * , # |
| Fold‐change AUC0–4 hr | 1.0 | 1.7 | 0.5 |
| C max (ng·ml−1) | 816 ± 258 | 1,187 ± 236 | 666 ± 278 # |
| T max (hr) | 0.3 ± 0.1 | 0.5 ± 0.2 | 0.3 ± 0.1 |
| C brain (ng·g−1) | 4.6 ± 2.5 | 8.0 ± 1.6 | N.D. |
| Fold‐change C brain | 1.0 | 1.7 | N.A. |
| Brain‐to‐plasma ratio | 0.05 ± 0.02 | 0.04 ± 0.004 | N.A. |
| Fold‐change ratio | 1.0 | 0.8 | N.A. |
| C Liver, ng·g−1 | 930 ± 591 | 1,894 ± 450 * | 206 ± 78 # |
| Fold‐change C liver | 1.0 | 2.0 | 0.2 |
| C SI (ng·g−1) | 1,551 ± 925 | 4,131 ± 1,503 * | 418 ± 223 * , # |
| Fold‐change C SI | 1.0 | 2.7 | 0.3 |
| C testis (ng·g−1) | 50.4 ± 17.8 | 64.6 ± 14.0 | 21.6 ± 15.1 * , # |
| Fold‐change C testis | 1.0 | 1.3 | 0.3 |
| Testis‐to‐plasma ratio | 0.8 ± 0.5 | 0.3 ± 0.05 | 1.3 ± 0.6 |
| Fold‐change ratio | 1.0 | 0.4 | 1.6 |
Note. Data are given as mean ± SD (n = 6). Statistical analysis was applied after log transformation of linear data.
Abbreviations: AUC0–4 hr, area under plasma concentration–time curve; C brain, brain concentration. C liver, liver concentration; C max, maximum concentration in plasma; C SI, small intestine tissue concentration; C testis, testis concentration; N.A., not applicable; N.D., not detectable; SI, small intestine (tissue); T max, time point (hr) of maximum plasma concentration.
P < .01 compared with wild‐type mice.
P < .01 compared between Cyp3a −/− and Cyp3aXAV mice.