TABLE 1.
Pharmacokinetic/metric parameters estimated from NCA of total brain and plasma concentration-time profiles after administration of a single intravenous bolus of ponatinib (3 mg/kg) in FVB wild-type and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 3 to 4 at each time point)
Data are presented as mean or mean ± S.E.M, unless otherwise indicated.
| Metric/Parameters | Plasma |
Brain |
||
|---|---|---|---|---|
| FVB Wild-Type | Mdr1a/b(−/−)Bcrp1(−/−) | FVB Wild-Type | Mdr1a/b(−/−)Bcrp1(−/−) | |
| Cmax (µg/ml) | 1.2 ± 0.05 | 1.1 ± 0.08 | 1.8 ± 0.1 | 4.7 ± 0.2 |
| Tmax (h) | 0.25 | 0.25 | 0.25 | 2 |
| CL (ml/min per kilogram) | 12.3 | 11.1 | ||
| Vd (l/kg) | 3.2 | 3.4 | ||
| Half-life (h) | 3.0 | 3.5 | 3.3 | 3.6 |
| AUC(0→t) (h*μg/ml) | 4.0 ± 0.3 | 3.96 ± 0.1 | 4.27 ± 0.2 | 42.1 ± 1.2 |
| AUC(0→∞) (h*μg/ml) | 4.1 | 4.5 | 4.1 | 44.8 |
| AUC-based Kpa | 1.0 | 10.0 | ||
| AUC-based Kp,uub | 0.11 | 1.1 | ||
| Transient steady-state Kpc | 1.7 | 11.6 | ||
| Transient steady-state Kp,uud | 0.11 | 1.3 | ||
| AUC based DAe | 9.9 | |||
| Transient steady-state DAe | 6.9 | |||
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/Cp,tss) × (fu,brain/fu,plasma).
e
DA due to the lack of efflux transporters, or Kp,knockout/Kp,wild-type or Kp,uu,knockout/Kp,uu,wild-type.