Title | Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Laramy JK, Kim M, Gupta SK, Parrish KE, Zhang S, Bakken KK, Carlson BL, Mladek AC, Ma DJ, Sarkaria JN, Elmquist WF |
Journal | J Pharmacol Exp Ther |
Volume | 363 |
Issue | 2 |
Pagination | 136-147 |
Date Published | 2017 11 |
ISSN | 1521-0103 |
Keywords | Animals, Antineoplastic Agents, Brain, Brain Neoplasms, Cell Survival, Dose-Response Relationship, Drug, Female, Glioblastoma, HEK293 Cells, Humans, Imidazoles, Male, Mice, Mice, Nude, Protein Binding, Protein Kinase Inhibitors, Pyridazines, Random Allocation, Treatment Outcome, Xenograft Model Antitumor Assays |
Abstract | 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 (IC). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6. |
DOI | 10.1124/jpet.117.243477 |
Alternate Journal | J. Pharmacol. Exp. Ther. |
PubMed ID | 28847917 |
PubMed Central ID | PMC5625285 |
Grant List | R01 NS073610 / NS / NINDS NIH HHS / United States R01 NS077921 / NS / NINDS NIH HHS / United States P50 CA108961 / CA / NCI NIH HHS / United States R01 CA138437 / CA / NCI NIH HHS / United States U54 CA210180 / CA / NCI NIH HHS / United States |