A neuropharmacokinetic assessment of bafetinib, a second generation dual BCR-Abl/Lyn tyrosine kinase inhibitor, in patients with recurrent high-grade gliomas

Abstract

Purpose: The primary objective of this study was to use intracerebral microdialysis (ICMD) to determine the neuropharmacokinetics of bafetinib, a dual BCR-Abl/Lyn tyrosine kinase inhibitor that may have activity against gliomas.

Methods: A microdialysis catheter was placed into either peritumoural or enhancing brain tissue of seven patients at the time of tumour resection or biopsy. Twenty-four hours later, bafetinib was administered, 240 or 360 mg po, repeating the same dose 12 h later. Dialysate samples were continuously collected for 24h, with plasma samples obtained in parallel. One to two weeks after finishing ICMD, patients were allowed to resume taking bafetinib continuously while being observed for toxicity and tumour response.

Results: Twenty-six dialysate samples per patient were collected (n=6) and analysed for bafetinib by tandem mass spectrometry. Bafetinib concentrations in the brain were below the lower limit of detection of the assay (0.1 ng/ml) in all samples except one from a single subject that was 0.52 ng/ml. The mean plasma bafetinib maximum concentrations after dose 1 and 2 were 143±99 and 247±73 ng/ml, respectively. Only one patient remained on treatment past two cycles, and no radiographic responses were seen.

Conclusions: Bafetinib does not sufficiently cross intact or disrupted blood-brain barrier, and therefore, systemic administration of bafetinib is not recommended when investigating this drug as a treatment for brain tumours. ICMD can be a valuable research tool in early drug development. Lead-in ICMD studies can be performed relatively quickly, requiring only a small number of patients, and without significantly disrupting standard cancer care.

Trial registration: ClinicalTrials.gov NCT01234740.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Fused images of a non-contrast head CT scan and a T1 post-contrast brain MRI of a study patient who underwent a gross total resection of tumor in the left frontal lobe. The CT scan was performed after the catheter was inserted to confirm correct placement of the catheter, and the MRI was performed on post-operative day 1. Images were autoregistered with mutual information matching algorithm using Varian Eclipse version 10.0 treatment planning system. The blended image is shown. A gold filament at the tip of the microdialysis catheter (arrow) is visible as bright signal on the CT scan but not visible on the T1 post-contrast MRI. Fused CT and T1 post-contrast MRI shows that the tip of the microdialysis catheter is placed in non-enhancing brain.

Figure 1

Fused images of a non-contrast head CT scan and a T1 post-contrast brain MRI of a study patient who underwent a biopsy of tumor in the right parietal lobe. The CT scan was performed after the catheter was inserted to confirm correct placement of the catheter, and the MRI was performed on post-operative day 1. Images were autoregistered with mutual information matching algorithm using Varian Eclipse version 10.0 treatment planning system. The blended image shows the gold filament of the catheter tip (arrow) as bright signal adjacent to enhancing brain tissue. The 3 mm gold tip is anterior to the 10 mm semi-permeable membrane (not visible on CT scan or MRI), which is in enhancing brain tissue.

Figure 2

Plot of the bafetinib plasma concentration versus time following the first 2 oral doses taken 12 hours apart. Solid circles are the mean concentrations at each time point, and the error bars are the standard deviations.