Pharmacokinetic/metric parameters determined by NCA of total brain and plasma concentration-time profiles after a single oral dose (30 mg/kg) of ponatinib in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 4 at each time point)
Data are presented as the mean or mean ± S.E.M, unless otherwise indicated. Data for the wild-type mice were previously reported (Laramy et al., 2017) and are included in this present study to compare with the three other genotypes that lack efflux transporters.
| Metric/Parameters | Plasma | Brain | ||||||
|---|---|---|---|---|---|---|---|---|
| FVB Wild-Type | Bcrp1(−/−) | Mdr1a/b(−/−) | Mdr1a/b(−/−)Bcrp1(−/−) | FVB Wild-Type | Bcrp1(−/−) | Mdr1a/b(−/−) | Mdr1a/b(−/−)Bcrp1(−/−) | |
| Cmax (µg/ml) | 1.1 ± 0.1 | 0.98 ± 0.2 | 1.5 ± 0.4 | 1.0 ± 0.04 | 0.96 ± 0.07 | 1.0 ± 0.09 | 5.1 ± 0.7 | 13.1 ± 0.8 |
| Tmax (h) | 2 | 4 | 2 | 4 | 2 | 8 | 4 | 4 |
| CL/F (ml/min per kilogram) | 46.6 | 48.2 | 39.1 | 43.3 | ||||
| Vd/F (l/kg) | 17.6 | 25.4 | 19.6 | 20.0 | ||||
| Half-life (h) | 4.4 | 6.1 | 5.8 | 5.3 | 5.7 | 6.6 | 4.3 | 5.5 |
| AUC(0→t) (h*μg/ml) | 10.4 ± 0.6 | 9.5 ± 0.8 | 12.1 ± 0.8 | 10.8 ± 0.6 | 8.3 ± 0.7 | 12.5 ± 0.7 | 45.0 ± 3.1 | 151.1 ± 7.4 |
| AUC(0→∞) (h*μg/ml) | 10.7 | 10.4 | 12.8 | 11.5 | 8.8 | 13.7 | 46.4 | 163.6 |
| AUC-based Kpa | 0.82 | 1.3 | 3.6 | 14.2 | ||||
| AUC-based Kp,uub | 0.11 | 0.14 | 0.40 | 1.6 | ||||
| Transient steady-state Kpc | 0.87 | 1.6 | 4.9 | 12.7 | ||||
| Transient steady-state Kp,uud | 0.11 | 0.18 | 0.54 | 1.4 | ||||
| AUC-based DAe | 1.6 | 4.4 | 17.3 | |||||
| Transient steady-state DAe | 1.9 | 5.7 | 14.6 | |||||
↵a Calculated by [AUC(0–∞),brain]/[AUC(0–∞),plasma].
↵b Calculated by [AUC(0–∞),brain]/[AUC(0–∞),plasma] × [fu,brain/fu,plasma].
↵c Calculated by Cmax,brain/corresponding plasma concentration at that time (Cp,tss).
↵d Calculated by [Cmax,brain/corresponding plasma concentration at that time (Cp,tss)] × (fu,brain/fu,plasma).
↵e DA due to lack of transporters, or Kp,knockout/Kp,wild-type or Kp,uu,knockout/Kp,uu,wild-type.