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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Fluids and Barriers of the CNS 1/2018

The effect of an adenosine A2A agonist on intra-tumoral concentrations of temozolomide in patients with recurrent glioblastoma

Zeitschrift:
Fluids and Barriers of the CNS > Ausgabe 1/2018
Autoren:
Sadhana Jackson, Jon Weingart, Edjah K. Nduom, Thura T. Harfi, Richard T. George, Dorothea McAreavey, Xiaobu Ye, Nicole M. Anders, Cody Peer, William D. Figg, Mark Gilbert, Michelle A. Rudek, Stuart A. Grossman
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12987-017-0088-8) contains supplementary material, which is available to authorized users.

Abstract

Background

The blood–brain barrier (BBB) severely limits the entry of systemically administered drugs including chemotherapy to the brain. In rodents, regadenoson activation of adenosine A2A receptors causes transient BBB disruption and increased drug concentrations in normal brain. This study was conducted to evaluate if activation of A2A receptors would increase intra-tumoral temozolomide concentrations in patients with glioblastoma.

Methods

Patients scheduled for a clinically indicated surgery for recurrent glioblastoma were eligible. Microdialysis catheters (MDC) were placed intraoperatively, and the positions were documented radiographically. On post-operative day #1, patients received oral temozolomide (150 mg/m2). On day #2, 60 min after oral temozolomide, patients received one intravenous dose of regadenoson (0.4 mg). Blood and MDC samples were collected to determine temozolomide concentrations.

Results

Six patients were enrolled. Five patients had no complications from the MDC placement or regadenoson and had successful collection of blood and dialysate samples. The mean plasma AUC was 16.4 ± 1.4 h µg/ml for temozolomide alone and 16.6 ± 2.87 h µg/ml with addition of regadenoson. The mean dialysate AUC was 2.9 ± 1.2 h µg/ml with temozolomide alone and 3.0 ± 1.7 h µg/ml with regadenoson. The mean brain:plasma AUC ratio was 18.0 ± 7.8 and 19.1 ± 10.7% for temozolomide alone and with regadenoson respectively. Peak concentration and Tmax in brain were not significantly different.

Conclusions

Although previously shown to be efficacious in rodents to increase varied size agents to cross the BBB, our data suggest that regadenoson does not increase temozolomide concentrations in brain. Further studies exploring alternative doses and schedules are needed; as transiently disrupting the BBB to facilitate drug entry is of critical importance in neuro-oncology.
Zusatzmaterial
Additional file 1. Pharmacokinetics of plasma and brain dialysate sampling post temozolomide and regadenoson.
Additional file 2. Individual temozolomide concentrations within non-contrast enhancing brain interstitium on a log based scale (A). Contrast-enhancing brain interstitium values in patients 1 and 3 (B). Solid line demonstrates treatment with temozolomide alone. Dashed line demonstrates combined treatment with regadenoson.
Literatur
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