Article Figures & Data
Figures
- Fig. 1.
A compartmental BBB model was adapted from the literature (Wang and Welty, 1996; Hammarlund-Udenaes et al., 1997) to describe drug movement between plasma and brain tissue after administration of a single intravenous bolus or oral dose. (A) An open two-compartment model described the total drug concentration-time profile in plasma with the parameters (k12, k21, k10, and/or Ka) that were used to generate a forcing function. The forcing function was subsequently input and used in the BBB model, which simultaneously described the Cplasma and Cbrain values. (B) A BBB model for free (unbound) drug in plasma and brain compartments. Xperipheral, total drug amount in the peripheral compartment.
- Fig. 2.
Total plasma (solid line with square) concentration and brain (dashed line with circle) concentration in wild-type mice (A) and Mdr1a/b(−/−)Bcrp1(−/−) mice (B), and brain-to-plasma ratio time course of ponatinib after administration of a single intravenous bolus (3 mg/kg) in FVB wild-type and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 3 to 4 at each time point) (C). Data are presented as the mean ± S.D.
- Fig. 3.
Total plasma (solid line with square) and brain (dashed line with circle) concentration-time profiles after administration of a single oral dose (30 mg/kg) of ponatinib in FVB wild-type (A), Bcrp1(−/−) (B), Mdr1a/b(−/−) (C), and Mdr1a/b(−/−)Bcrp1(−/) (D) mice (N = 4 at each time point). Data are presented as mean ± S.D. Data for the wild-type mice were previously reported (Laramy et al., 2017) and included in this present study to compare the wild-type genotype with the three other genotypes that lack efflux transporters.
- Fig. 4.
Total brain-to-plasma ratio profiles after administration of a single oral dose (30 mg/kg) in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 4 at each time point). Data are presented as the mean ± S.D. Data for the wild-type were previously reported (Laramy et al., 2017) and were included in this present study to compare the wild-type genotype with the three other genotypes that lack efflux transporters.
- Fig. 5.
Total steady-state plasma and brain concentrations (A) and corresponding total steady-state brain-to-plasma ratios (B) of ponatinib after continuous intraperitoneal infusion (40 µg/h) for 48 hours in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 4 in each genotype) (*P < 0.05; *statistical significance). Data are presented as the mean ± S.D.
- Fig. 6.
Observed (red square) and model-predicted (red solid line) total plasma concentration-time profiles, and observed (black circle) and model-predicted (black dashed line) total brain concentration-time profiles in FVB wild-type (A) and Mdr1a/b(−/−)Bcrp1(−/−) (B) mice (N = 3 to 4 at each time point) after a single intravenous bolus (3 mg/kg). The observed data are presented as the mean ± S.D.
- Fig. 7.
Observed (red square) and model-predicted (red solid line) total plasma concentration-time profiles, and observed (black circle) and model-predicted (black dashed line) total brain concentration-time profiles in FVB wild-type (A), Bcrp1(−/−) (B), Mdr1a/b(−/−) (C), and Mdr1a/b(−/−)Bcrp1(−/−) (D) mice (N = 4 at each time point) after a single oral dose (30 mg/kg). The observed data are presented as the mean ± S.D. The observed data for the wild-type were previously reported (Laramy et al., 2017) and were included in this present study to compare with the three other genotypes that lack efflux transporters.
Tables
- 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.
- TABLE 2
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.
- TABLE 3
Steady-state plasma and brain concentration, brain-to-plasma ratio, and distribution advantage of ponatinib after continuous intraperitoneal infusion (40 µg/h) for 48 h in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) mice (N = 4 in each genotype)
Data are presented as the mean ± S.D, unless otherwise indicated.
Mice Steady-State Total Concentration (μg/ml) Kp Kp,uua DAb Plasma Brain FVB wild-type 0.72 ± 0.66 0.53 ± 0.37 1.0 ± 0.51 0.11 ± 0.056 Bcrp1(−/−) 0.42 ± 0.21 0.71 ± 0.30 1.8 ± 0.26 0.20 ± 0.029 1.7 Mdr1a/b(−/−) 0.39 ± 0.14 1.3 ± 0.70 3.8 ± 2.5 0.42 ± 0.28 3.7 Mdr1a/b(−/−)Bcrp1(−/−) 0.40 ± 0.34 6.1 ± 5.0* 15.6 ± 2.6* 1.7 ± 0.29* 15.0 - TABLE 4
Data summary: comparison of the Kp estimates among different routes of administration, including a single intravenous bolus (3 mg/kg, i.v.; N = 3 to 4 at each time point), an oral dose (30 mg/kg, PO; N = 4 at each time point), or a continuous steady-state intraperitoneal infusion (40 µg/h, i.p.; N = 4 in each genotype)
Data are presented as the mean. Data for the wild-type genotype after administration of a single oral dose 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.
Genotype Kpa DAb i.v. PO i.p. i.v. PO i.p. A B A B C A B A B C FVB wild-type 1.0 1.7 0.82 0.87 1.0 — — — — — Bcrp1(−/−) — — 1.3 1.6 1.8 — — 1.6 1.9 1.7 Mdr1a/b(−/−) — — 3.6 4.9 3.8 — — 4.4 5.7 3.7 Mdr1a/b(−/−) — — — — — — — — — — Bcrp1(−/−) 10.0 11.6 14.2 12.7 15.6 9.9 6.9 17.3 14.6 15.0 - TABLE 5
Pharmacokinetic parameters obtained from an open two-compartment model that described the total plasma concentration-time profiles from naive-pooled analysis of all genotypes (N = 4 at each time point) after a single intravenous bolus (3 mg/kg) or oral dose (30 mg/kg)
The parameters are presented as the mean estimate.
Mean CV% 95% Confidence Interval Estimated parameters Vcentral (ml/kg) 1478.3 8.1 (964.8, 1991.9) K10 (h−1) 0.47 6.4 (0.34, 0.60) K21 (h−1) 2.34 19.2 (0.41, 4.3) K12 (h−1) 2.15 10.4 (1.2, 3.1) Kelim (h−1) 0.21 1.7 (0.20, 0.23) Ka (h−1) 0.28 11.5 (0.20, 0.36) Calculated parameters Vu,central (l/kg) 645.8 CLsystemic (ml/min per kilogram) 5.2 1.7 (4.8, 5.6) Half-life (h)a 3.3 1.7 (3.0, 3.5) ↵a Half-life of ponatinib (total drug) from the systemic circulation (body).
- TABLE 6
Pharmacokinetic parameters obtained from the compartmental BBB model describing the brain and plasma concentration-time after administration of a single intravenous bolus (3 mg/kg, i.v.; N = 3 to 4 at each time point) or oral dose (30 mg/kg, PO; N = 4 at each time point) in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and/or Mdr1a/b(−/−)Bcrp1(−/−) mice
Fixed values are left as blank (—). The parameters are presented as the mean estimate.
Route of Administration Genotype Parameters kin (h−1) kout (h−1) MTTbrain (h)a CLin (ml/h per kilogram) CLout (ml/h per kilogram) CLu,in (ml/h per kilogram) CLu,out (ml/h per kilogram) Mean CV (%) Mean CV (%) Mean Mean CV (%) Mean CV (%) Mean CV (%) Mean CV (%) Intravenous WT 4.0 × 10−5 — 7.7 10.2 0.13 0.059 — 0.066 36.6 25.8 — 225.8 22.5 TKO 4.0 × 10−5 11.2 0.64 14.0 1.6 0.059 13.8 0.0055 37.9 25.8 11.2 18.7 24.4 By mouth WT 5.5 × 10−5 — 12.4 2.7 0.081 0.081 — 0.11 35.3 35.2 — 361.6 20.2 Bcrp-KO 5.5 × 10−5 — 8.2 18.2 0.12 0.081 — 0.070 39.6 35.2 — 239.4 27.0 Pgp-KO 5.5 × 10−5 — 2.9 26.0 0.34 0.081 — 0.025 43.8 35.2 — 85.1 32.8 TKO 5.5 × 10−5 16.2 0.65 15.7 1.5 0.081 18.1 0.0056 38.5 35.2 16.2 19.0 25.5 Bcrp-KO, Bcrp1(−/−); KO, knockout; Pgp-KO, Mdr1a/b(−/−); TKO, Mdr1a/b(−/−)Bcrp1(−/−); WT, wild-type.
↵a Calculated by 1/kout.
- TABLE 7
The Kp,pred and Kp,uu,pred values and the DA,pred values, using the pharmacokinetic parameters obtained from the compartmental BBB model describing the brain and plasma concentration-time profiles after administration of a single intravenous bolus (3 mg/kg, i.v.; N = 3 to 4 at each time point) or oral dose (30 mg/kg, PO; N = 4 at each time point) in FVB wild-type, Bcrp1(−/−), Mdr1a/b(−/−), and/or Mdr1a/b(−/−)Bcrp1(−/−) mice
The parameters are presented as the mean estimate.
Route of Administration Genotype Parameters AUC(0→∞),predicted (Mean Estimate) h*μg/ml Transient Steady State (Mean Estimate) μg/ml Clearance Based (Mean Estimate) AUC(0→∞),plasma AUC(0→∞),brain Kp,preda DA,predb Cp,tss(µg/ml) Cmax, brain Kp,preda DA,predb Kp,preda Kp,uu,predc DA,predb Intravenous WT 4.0 3.6 0.89 1.2 1.1 0.89 0.89 0.11 TKO 4.0 43.1 10.7 12 0.5 5.3 10.8 12.0 10.7 1.4 12.1 By mouth WT 10.9 8.2 0.76 1.2 0.95 0.76 0.76 0.097 Bcrp-KO 10.6 12.2 1.1 1.5 1.1 1.2 1.1 1.5 1.1 0.15 1.5 Pgp-KO 11.2 35.9 3.2 4.2 1.1 3.4 3.2 4.2 3.2 0.41 4.2 TKO 10.7 152.3 14.3 18.8 1.0 12.9 13.4 17.7 14.4 1.9 19.1
