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Predicting In Vivo Payloads Delivery using a Blood-brain Tumor-barrier in a Dish
Published on: April 16, 2019
Panobinostat penetrates the blood-brain barrier and achieves effective brain concentrations in a murine model
Morgan J Homan1, Andrea Franson2, Karthik Ravi2
1Department of Clinical Pharmacy and Pharmacy Services, University of Michigan College of Pharmacy, 1540 E. Hospital Dr., CW 7-251B, Ann Arbor, MI, 48109-5008, US.
Purpose:
Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model.
Methods:
Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC-MS was performed to quantify panobinostat concentrations. Cmax and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines.
Results:
Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated Cmax in humans is expected to be significantly higher than the IC-50 identified in DIPG models.
Conclusion:
It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.
Insights
Panobinostat effectively crosses the blood-brain barrier (BBB) in mice, reaching concentrations higher than those needed to inhibit DIPG cells. This suggests potential efficacy for panobinostat in treating brain tumors like DIPG.
Area of Science:
- Pharmacology
- Neuro-oncology
- Drug Discovery
Background:
- Panobinostat is an orally bioavailable pan-histone deacetylase (HDAC) inhibitor with demonstrated anti-cancer activity.
- Pediatric brain tumors, including diffuse intrinsic pontine glioma (DIPG), are challenging to treat due to limited therapeutic options and drug penetration into the central nervous system (CNS).
Purpose of the Study:
- To investigate the blood-brain barrier (BBB) penetration of panobinostat in a murine model.
- To determine if panobinostat achieves therapeutic concentrations within the brain relevant to its efficacy against H3K27M mutant cell lines.
Main Methods:
- Panobinostat was administered intravenously to CD-1 female mice at a dose of 15 mg/kg.
- Blood and brain samples were collected at various time points post-administration.
- Liquid chromatography-mass spectrometry (LC-MS) was used to quantify panobinostat concentrations.
Main Results:
- Panobinostat was detected in both plasma and brain tissue of mice.
- The brain-to-plasma ratio of panobinostat was 2.22 at 1 hour, and the brain to plasma AUC ratio was 2.63.
- Achieved brain concentrations are expected to exceed the IC-50 values for DIPG cell lines.
Conclusions:
- Panobinostat demonstrates significant BBB penetration in a murine model.
- The drug achieves concentrations in the brain that are potentially therapeutic for CNS tumors, including DIPG.
- Further clinical investigation of panobinostat for brain tumor treatment is warranted.
