An in vitro study was done to estimate the fractional recovery of eribulin by the microdialysis catheter. This in vitro assessment was performed with the same microdialysis equipment that would be used in the clinical trial. A microdialysis catheter with a molecular weight cutoff of 20 kDa (70 Brain MD Catheter; membrane length 10 mm, shaft length 100 mm; ref. no. P000050, M Dialysis) was placed into a reservoir containing a solution with a known concentration of eribulin. Artificial CSF (Perfusion Fluid CNS; ref. no. P000151, M Dialysis) perfused the microdialysis catheter at a flow rate of 1 µL/min while serial dialysate samples were collected.

The City of Hope Analytical Pharmacology Core Facility developed a quantitative assay for eribulin [17], and concentrations of eribulin in dialysate samples were determined by liquid chromatography/tandem mass spectrometry. The lower limit of detection of eribulin in brain extracellular fluid was set to 0.02 ng/ml. Recovery of eribulin by the microdialysis catheter at a flow rate of 1 µL/min was 100%, and so that was the flow rate used in the clinical trial.

Eligible patients were at least 18 years old, had either metastatic or primary brain tumor(s), and were planning to undergo resection of tumor. There was no limit to the number of prior treatments (any type of brain radiation, surgery, or chemotherapy) for their brain tumor(s). Adequate organ function was required and if corticosteroids were needed for controlling cerebral edema, patients had to be on a stable dose for at least 1 week prior to study enrollment. Participants also had to have a Karnofsky performance score ≥ 60.

The primary objective of the study was to determine the neuropharmacokinetic profile of eribulin using intracerebral microdialysis. The secondary objective was to compare concentrations of eribulin in brain tissue where the blood–brain barrier was disrupted versus intact. This objective was accomplished by fusing the T1 post-contrast images from a participant’s post-operative brain MRI with their post-operative non-contrast CT scan of the brain in which the gold filament at the tip of the microdialysis catheter is visible. Thus we were able to know if the tip of a microdialysis catheter had been placed in contrast enhancing brain tissue (indicating the presence of disrupted blood–brain barrier) or non-enhancing brain tissue (indicating the blood–brain barrier was intact in that area) [Fig. 1].

a Study Schema. During the surgery, after resection of tumor two microdialysis catheters were inserted in residual tumor and/or peritumoral brain tissue, as was technically feasible. Twenty four hours later a 1.4 mg/m2 dose of eribuin was admnistered to the patient intravenously. Serial dialysate and blood samples were collected during the following 48 h. b Representative post-operative imaging (from Participant 4). Top: gold tips of the microdialysis catheters are visible on a non-contrast CT scan. Bottom: merging of corresponding images from the participant’s post-operative non-contrast brain CT and MRI (T1 post-contrast sequence) scans show that one of the microdialysis catheter tips was placed in contrast-enhancing brain tissue (residual tumor) and the other one was placed in non-enhancing brain tissue (normal brain)

During the surgery, after resection of tumor the neurosurgeon inserted two 70 Brain MD Catheters in residual tumor and/or peritumoral brain tissue, as was technically feasible. After a post-operative non-contrast CT scan of the brain confirmed proper placement of the intracerebral microdialysis catheters in brain tissue, the inlet tubings of the catheters were connected to portable syringe pumps (107 Microdialysis Pump, ref. no. P000127, M Dialysis) that perfused the catheters with artificial CSF at a rate of 1 µL/min.

At least 24 h after surgery, participants were given a single 1.4 mg/m2 dose of eribulin intravenously. To determine the neuropharmacokinetics of eribulin, dialysate samples were continuously collected from the outlet tubing of the catheters for 72 h. The microvial at the end of the catheter’s outlet tubing was changed to a new one every 60 min during the first 24 h and then every 3 h until the end of the 72 h collection period. Blood samples for assessing the relationship between systemic drug exposure and intracerebral concentrations of eribulin were obtained prior to administering the dose of eribulin, at 5, 15, 30, and 60 min, and 2, 4, 6, 8, 12, 24, 48, and 72 h, and then 1 week later. At the end of the collection period, the microdialysis catheters were removed at the bedside. Concentrations of eribulin in dialysate and plasma samples were measured by liquid chromatography/ tandem mass spectrometry.

The clinical protocol for this non-therapeutic study was approved by the City of Hope Institutional Review Board and conducted in compliance with the ethical principles of the Declaration of Helsinki, the principles of Good Clinical Practice, and all applicable regulations.