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.
|Original language||English (US)|
|Number of pages||12|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Nov 2017|
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health [Grants R01 CA138437, R01 NS077921, U54 CA210180, and P50 CA108961]. J.K.L. was supported by the Edward G. Rippie, Rory P. Remmel and Cheryl L. Zimmerman in Drug Metabolism and Pharmacokinetics, and American Foundation for Pharmaceutical Education Pre-Doctoral Fellowships. https://doi.org/10.1124/jpet.117.243477. s This article has supplemental material available at jpet.aspetjournals.org.
Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.