Preclinical Comparison of the Blood-brain barrier Permeability of Osimertinib with Other EGFR TKIs
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Published on: November 22, 2021
Nicola Colclough1, Kan Chen2, Peter Johnström3,4
1DMPK, Early Oncology TDE, AstraZeneca, Cambridge, United Kingdom. nicola.colclough@astrazeneca.com.
Purpose:
Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood-brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.
Experimental Design:
We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models.
Results:
In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (C max %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.
Conclusions:
These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.
Insights
Osimertinib demonstrates superior blood-brain barrier penetration among EGFR-TKIs, showing significant brain exposure and efficacy in preclinical models for brain metastases. This supports its clinical use in EGFR-mutant brain disease.
Area of Science:
- Pharmacology
- Neuroscience
- Oncology
Background:
- Metastatic brain disease is a significant challenge in EGFR-mutant lung cancer.
- Blood-brain barrier (BBB) penetration is crucial for treating brain metastases.
- Osimertinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) targeting specific mutations.
Purpose of the Study:
- To evaluate the brain penetration of osimertinib and other EGFR-TKIs.
- To compare the efficacy of osimertinib versus afatinib in preclinical brain metastasis models.
- To establish the correlation between in vitro transporter efflux and in vivo BBB penetration.
Main Methods:
- In vitro assessment of EGFR-TKIs as substrates for human BBB efflux transporters.
- In vivo studies using rat free brain to free plasma ratios (Kpuu).
- Positron Emission Tomography (PET) imaging in Cynomolgus macaques.
- Mass spectroscopy imaging in mouse models of brain macrometastases and subclinical metastases.
Main Results:
- Osimertinib exhibited the lowest efflux ratio in vitro, indicating minimal transporter interaction.
- Osimertinib showed the highest BBB penetrance in vivo (Kpuu = 0.21) compared to other TKIs (Kpuu ≤ 0.12).
- PET imaging confirmed significant brain penetrance for osimertinib in macaques, with notable distribution in mouse brain tumor models.
Conclusions:
- Osimertinib achieves substantial brain exposure compared to other tested EGFR-TKIs.
- These findings support the clinical investigation of osimertinib for EGFR-mutant brain metastases.
- In vitro transporter efflux assays can serve as an early screening tool for predicting in vivo brain penetrance in drug discovery.
