RT Journal Article SR Electronic T1 Heterogeneous binding and CNS distribution of the multi-targeted kinase inhibitor ponatinib restrict orthotopic efficacy in a patient-derived xenograft model of glioblastoma JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.117.243477 DO 10.1124/jpet.117.243477 A1 Janice K Laramy A1 Minjee Kim A1 Shiv K Gupta A1 Karen E Parrish A1 Shuangling Zhang A1 Katrina K Bakken A1 Brett L Carlson A1 Ann C Mladek A1 Daniel J Ma A1 Jann N Sarkaria A1 William F. Elmquist YR 2017 UL http://jpet.aspetjournals.org/content/early/2017/08/28/jpet.117.243477.abstract AB This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multi-kinase inhibitor ponatinib in a patient-derived xenograft (PDX) 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, in spite of 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 to 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 post dose. 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.