Article Figures & Data
Figures
- Fig. 1.
Rationale for ATM inhibition using AZD1390 for radiosensitization of tumor cells.
- Fig. 2.
Need for the development of brain-penetrant ATM inhibitors for radiosensitization in GBM. (A) Incomplete surgical resection due to invasive nature of GBM leads to tumor recurrence. (B) Ability to target tumor cells residing behind a relatively intact BBB in normal brain for effective treatment.
- Fig. 3.
Pharmacokinetics of AZD1390 after intravenous administration. Data represent mean ± S.D. (n = 4). Concentration-time profiles of AZD1390 in (A) plasma, (B) brain, and (C) spinal cord after a single intravenous bolus dose of 5 mg/kg in FVB wild-type, BKO, PKO, and TKO mice.
- Fig. 4.
Brain-to-plasma and spinal cord-to-plasma ratios after intravenous administration. Data represent mean ± S.D. (n = 4). (A) Brain-to-plasma ratio and (B) spinal cord-to-plasma ratio over time after a single intravenous bolus dose of 5 mg/kg in in FVB wild-type, BKO, PKO and TKO mice.
- Fig. 5.
Pharmacokinetics of AZD1390 after oral administration. Data represent mean ± S.D. (n = 4). Plasma, brain, and spinal cord concentrations of AZD1390 in (A) FVB wild-type, and (B) TKO mice; brain-to-plasma and spinal cord-to-plasma ratios of AZD1390 with time in (C) FVB wild-type and (D) TKO mice after a single oral dose of 10 mg/kg.
- Fig. 6.
Impact of efflux inhibition using elacridar in FVB wild-type mice. Data represent mean ± S.D., n = 4. *P < 0.05. (A) Plasma, brain and spinal cord concentrations; (B) Kpbrain and Kp spinal cord; and (C) Kpuu,brain and Kpuu,spinal cord at 2 hours after coadministration of 10 mg/kg oral AZD1390 and 10 mg/kg intraperitoneal elacridar in wild-type mice.
- Fig. 7.
Impact of efflux inhibition using elacridar in TKO mice. Data represent mean ± S.D. (n = 4). *P < 0.05. (A) Plasma, brain and spinal cord concentrations; (B) Kpbrain and Kp spinal cord; and (C) Kpuu,brain and Kpuu,spinal cord at 2 hours after coadministration of 10 mg/kg oral AZD1390 and 10 mg/kg intraperitoneal elacridar in TKO mice.
- Fig. 8.
CNS regional distribution of AZD1390 after steady-state infusion. Data represent mean ± S.D. (n = 4 to 5). *P < 0.05. (A) Concentration of AZD1390 within the cortex, cerebellum, hypothalamus and thalamus, brain stem, spinal cord, and plasma; (B) regional Kp; and (C) regional Kpuu of AZD1390 within the cortex, cerebellum, hypothalamus and thalamus, brain stem, and spinal cord in FVB-wild type, BKO, PKO, and TKO mice after a steady-state infusion of 10 μg/h for 24 hours.
- Fig. 9.
Tumor distribution of AZD1390 in GBM 12 PDX mouse brains. Data represent mean ± S.D. (n = 4 to 5). *P < 0.05. (A) Brain slice used for tumor carving; (B) concentration in plasma, tumor core, tumor rim, and normal brain; and (C) Kp in tumor core, tumor rim, and normal brain in GBM 12 tumor–bearing mouse brains dosed with 20 mg/kg of AZD1390 and harvested at 4 and 12 hours.
- Fig. 10.
Key factors to be considered in the development of ATM inhibitors for brain tumors.
Tables
- TABLE 1
Summary of pharmacokinetic parameters in plasma, brain, and spinal cord in FVB wild-type, BKO, PKO, and TKO mice after an intravenous bolus dose of 5 mg/kg AZD1390
Parameter Units Plasma Brain Spinal Cord Wild-Type Bcrp1−/− Mdr1a/b−/− Mdr1a/b−/− Bcrp1−/− Wild-Type Bcrp1 −/− Mdr1a/b−/− Mdr1a/b−/− Bcrp1−/− Wild-Type Bcrp1−/− Mdr1a/b−/− Mdr1a/b−/− Bcrp1−/− t1/2 hour 2.6 2.4 2.8 2.5 2.0 1.8 3.0 2.4 2.1 2.1 2.7 2.5 CL l/hr/kg 0.95 0.88 0.97 0.92 Vss l/kg 2.7 2.7 3.0 2.9 AUC0–∞ hr*ng/ml 5261 ± 295 5690 ± 197 5178 ± 361 5452 ± 306 1542 ± 111 1814 ± 97 16,221 ± 752 17,043 ± 684 1684 ± 129 1960 ± 128 13,949 ± 718 16,566 ± 445 Kp 0.29 0.32 3.13 3.13 0.32 0.34 2.7 3.03 fu 0.203 ± 0.025 0.075 ± 0.002 0.11 ± 0.008 Kpuu 0.1 0.12 1.16 1.16 0.17 0.18 1.46 1.64 DAfree 1 1.2 11.6 11.6 1 1.1 8.6 9.6 - TABLE 2
Summary of pharmacokinetic parameters in plasma, brain, and spinal cord in FVB wild-type and TKO mice after a single oral dose of 10 mg/kg AZD1390
Parameter Units Plasma Brain Spinal Cord Wild-Type Mdr1a/b−/− Bcrp1−/− Wild-Type Mdr1a/b−/− Bcrp1−/− Wild-Type Mdr1a/b−/− Bcrp1−/− Tmax hour 1 0.5 2 2 2 2 Cmax ng/ml 1523 ± 435 1367 ± 207 215 ± 11 3925 ± 599 104 ± 14 2491 ± 404 t1/2 hour 3.4 3.3 3.4 2.8 3.9 2.8 CL/F l/hr/kg 2.2 1.9 Vd/F l/kg 10.7 9.0 AUC0-∞ hr*ng/ml 4543 ± 538 5313 ± 795 1440 ± 131 19,783 ± 1378 1057 ± 224 13,410 ± 967 Oral Bioavailability 0.43 0.48 Kp 0.32 3.72 0.23 2.52 Kpuu 0.12 1.37 0.12 1.37 DAfree 1 11.4 1 11.4 Tmax, time to reach Cmax.
