Entrectinib, a TRK/ROS1 inhibitor with anti-CNS tumor activity: differentiation from other inhibitors in its class due to weak interaction with P-glycoprotein.
CNS-active
P-gp
ROS1
TRK
entrectinib
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
09 06 2020
09 06 2020
Historique:
pubmed:
10
5
2020
medline:
28
4
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
Studies evaluating the CNS penetration of a novel tyrosine kinase inhibitor, entrectinib, proved challenging, particularly due to discrepancies across earlier experiments regarding P-glycoprotein (P-gp) interaction and brain distribution. To address this question, we used a novel "apical efflux ratio" (AP-ER) model to assess P-gp interaction with entrectinib, crizotinib, and larotrectinib, and compared their brain-penetration properties. AP-ER was designed to calculate P-gp interaction with the 3 drugs in vitro using P-gp-overexpressing cells. Brain penetration was studied in rat plasma, brain, and cerebrospinal fluid (CSF) samples after intravenous drug infusion. Unbound brain concentrations were estimated through kinetic lipid membrane binding assays and ex vivo experiments, while the antitumor activity of entrectinib was evaluated in a clinically relevant setting using an intracranial tumor mouse model. Entrectinib showed lower AP-ER (1.1-1.15) than crizotinib and larotrectinib (≥2.8). Despite not reaching steady-state brain exposures in rats after 6 hours, entrectinib presented a more favorable CSF-to-unbound concentration in plasma (CSF/Cu,p) ratio (>0.2) than crizotinib and larotrectinib at steady state (both: CSF/Cu,p ~0.03). In vivo experiments validated the AP-ER approach. Entrectinib treatment resulted in strong tumor inhibition and full survival benefit in the intracranial tumor model at clinically relevant systemic exposures. Entrectinib, unlike crizotinib and larotrectinib, is a weak P-gp substrate that can sustain CNS exposure based on our novel in vitro and in vivo experiments. This is consistent with the observed preclinical and clinical efficacy of entrectinib in neurotrophic tropomyosin receptor kinase (NTRK) and ROS1 fusion-positive CNS tumors and secondary CNS metastases.
Sections du résumé
BACKGROUND
Studies evaluating the CNS penetration of a novel tyrosine kinase inhibitor, entrectinib, proved challenging, particularly due to discrepancies across earlier experiments regarding P-glycoprotein (P-gp) interaction and brain distribution. To address this question, we used a novel "apical efflux ratio" (AP-ER) model to assess P-gp interaction with entrectinib, crizotinib, and larotrectinib, and compared their brain-penetration properties.
METHODS
AP-ER was designed to calculate P-gp interaction with the 3 drugs in vitro using P-gp-overexpressing cells. Brain penetration was studied in rat plasma, brain, and cerebrospinal fluid (CSF) samples after intravenous drug infusion. Unbound brain concentrations were estimated through kinetic lipid membrane binding assays and ex vivo experiments, while the antitumor activity of entrectinib was evaluated in a clinically relevant setting using an intracranial tumor mouse model.
RESULTS
Entrectinib showed lower AP-ER (1.1-1.15) than crizotinib and larotrectinib (≥2.8). Despite not reaching steady-state brain exposures in rats after 6 hours, entrectinib presented a more favorable CSF-to-unbound concentration in plasma (CSF/Cu,p) ratio (>0.2) than crizotinib and larotrectinib at steady state (both: CSF/Cu,p ~0.03). In vivo experiments validated the AP-ER approach. Entrectinib treatment resulted in strong tumor inhibition and full survival benefit in the intracranial tumor model at clinically relevant systemic exposures.
CONCLUSIONS
Entrectinib, unlike crizotinib and larotrectinib, is a weak P-gp substrate that can sustain CNS exposure based on our novel in vitro and in vivo experiments. This is consistent with the observed preclinical and clinical efficacy of entrectinib in neurotrophic tropomyosin receptor kinase (NTRK) and ROS1 fusion-positive CNS tumors and secondary CNS metastases.
Identifiants
pubmed: 32383735
pii: 5834590
doi: 10.1093/neuonc/noaa052
pmc: PMC7283026
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B
0
ATP Binding Cassette Transporter, Subfamily B, Member 1
0
Benzamides
0
Indazoles
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins
0
Protein-Tyrosine Kinases
EC 2.7.10.1
entrectinib
L5ORF0AN1I
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
819-829Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
F1000Res. 2018 Nov 9;7:
pubmed: 30473769
Nat Commun. 2017 Jul 11;8:15987
pubmed: 28695888
N Engl J Med. 2014 Nov 20;371(21):1963-71
pubmed: 25264305
Mol Pharm. 2019 May 6;16(5):1851-1863
pubmed: 30933526
Eur J Pharm Sci. 2015 Nov 15;79:27-35
pubmed: 26341407
Drug Metab Dispos. 2014 Sep;42(9):1411-22
pubmed: 24939652
J Pharm Sci. 2003 May;92(5):967-74
pubmed: 12712416
N Engl J Med. 2018 Feb 22;378(8):731-739
pubmed: 29466156
J Med Chem. 2016 Apr 14;59(7):3392-408
pubmed: 27003761
Nat Commun. 2014 Sep 10;5:4846
pubmed: 25204415
Mol Cancer Ther. 2016 Apr;15(4):628-39
pubmed: 26939704
Ann Oncol. 2019 Jul 1;30(7):1121-1126
pubmed: 30980071
Neuro Oncol. 2018 Feb 19;20(3):307-312
pubmed: 29016919
Ann Oncol. 2016 Sep;27 Suppl 3:iii42-iii50
pubmed: 27573756
Trends Pharmacol Sci. 2016 Nov;37(11):904-932
pubmed: 27659854
Lancet Oncol. 2020 Feb;21(2):271-282
pubmed: 31838007
J Pharm Sci. 2011 Jun;100(6):2498-507
pubmed: 21213309
Mol Pharm. 2015 Dec 7;12(12):4529-41
pubmed: 26560069
J Clin Oncol. 2011 May 20;29(15):e443-5
pubmed: 21422405
Lancet Oncol. 2020 Feb;21(2):261-270
pubmed: 31838015
Radiat Oncol. 2011 Nov 25;6:166
pubmed: 22118497