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- W2907133739 endingPage "2025" @default.
- W2907133739 startingPage "2025" @default.
- W2907133739 abstract "2025 Background: Drug delivery is a major problem in the treatment of glioblastoma (GBM). Tumour pharmacokinetics (PK) of small molecule targeted agents in GBM are not well understood, and poor activity may result from lack of biological efficacy or adverse PK. Olaparib, a small molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), has potential to overcome treatment resistance of GBM. Despite radiological responses in brain metastases, GBM penetration by olaparib has not been studied. Methods: Preclinically, blood-brain barrier penetration was assessed by directional transport of [14C]-olaparib across MDCKII cells expressing MDR1 and autoradiography of rats and mice treated with [14C]-olaparib. Clinically, 8 patients with recurrent GBM underwent dynamic contrast enhanced (DCE) MRI at baseline followed by tumour resection after 4 days of oral olaparib (tablet: 100 mg QD, n=5; 200 mg BID, n=3). Olaparib levels were measured in tumour and plasma by LC-MS. Results: Olaparib was a substrate for MDR1 and efflux was blocked by the MDR1 inhibitor ketoconazole. Radioactivity was not detected in the central nervous systems (CNS) of rats or mice after single dose [14C]-olaparib, but significant levels were measured in subcutaneous HCT-116 tumour xenografts up to 96 hrs. Olaparib was detected in 24/24 resected GBM specimens from 8 patients (Table) at concentrations similar to those in previous breast cancer studies in which PARP inhibition and tumour responses were observed. Pre-treatment DCE-MRI showed increased vascular permeability in tumours, and tumour cellularity parameters correlated with olaparib levels. Conclusions: Olaparib is excluded from the CNS under normal conditions but reliably penetrates recurrent GBM at therapeutic levels. Small molecule PK in GBM are poorly predicted by standard pre-clinical models. Clinical trial information: NCT01390571. Subject Daily olaparib dose (mg) Olaparib concentration (day 4) Tumor section (ng/g) Mean tumor (ng/g) Plasma (ng/ml) 1 400 137 238 5290 210 367 2 400 71.2 94.7 3840 72.9 140 3 400 431 282 1330 133 281 4 100 177 112 876 105 55.0 5 100 324 364 773 354 413 6 100 494 413 617 345 401 7 100 53.1 59.8 1290 65.8 60.6 8 100 203 175 1460 156 166" @default.
- W2907133739 created "2019-01-11" @default.
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- W2907133739 date "2014-05-20" @default.
- W2907133739 modified "2023-10-16" @default.
- W2907133739 title "Results of stage 1 of the oparatic trial: A phase I study of olaparib in combination with temozolomide in patients with relapsed glioblastoma." @default.
- W2907133739 doi "https://doi.org/10.1200/jco.2014.32.15_suppl.2025" @default.
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