PT  - JOURNAL ARTICLE
AU  - Janice K. Laramy
AU  - Minjee Kim
AU  - Shiv K. Gupta
AU  - Karen E. Parrish
AU  - Shuangling Zhang
AU  - Katrina K. Bakken
AU  - Brett L. Carlson
AU  - Ann C. Mladek
AU  - Daniel J. Ma
AU  - Jann N. Sarkaria
AU  - William F. Elmquist
TI  - Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma
AID  - 10.1124/jpet.117.243477
DP  - 2017 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 136--147
VI  - 363
IP  - 2
4099  - http://jpet.aspetjournals.org/content/363/2/136.short
4100  - http://jpet.aspetjournals.org/content/363/2/136.full
SO  - J Pharmacol Exp Ther2017 Nov 01; 363
AB  - This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC50). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6.