Nicolas Tournier1, Sebastien Goutal2, Sylvain Auvity2, Alexander Traxl3, Severin Mairinger3, Thomas Wanek3, Ourkia-Badia Helal2, Irène Buvat2, Michael Soussan2, Fabien Caillé2, Oliver Langer3,4,5. 1. Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France nicolas.tournier@cea.fr. 2. Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France. 3. Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria. 4. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; and. 5. Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
Abstract
The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of 11C-erlotinib in nonhuman primates as a model of the human BBB. METHODS: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11C-erlotinib under baseline conditions (n = 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3). RESULTS: Under baseline conditions, 11C-erlotinib distribution to the brain (total volume of distribution [VT], 0.22 ± 0.015 mL/cm3) was markedly lower than its distribution to muscle tissue surrounding the skull (VT, 0.86 ± 0.10 mL/cm3). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in 11C-erlotinib distribution to the brain (VT, 0.81 ± 0.21 mL/cm3, P < 0.01), reaching levels comparable to those in muscle tissue, without changing 11C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (VT, 0.38 ± 0.033 mL/cm3, P < 0.05), with a concomitant increase in 11C-erlotinib plasma exposure. CONCLUSION: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.
The tyrosine kinase inhibitor erlotinib poorly penetrates the blood-brain barrier (BBB) because of efflux transport by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2), thereby limiting its utility in the treatment of non-small cell lung cancer metastases in the brain. Pharmacologic strategies to inhibit ABCB1/ABCG2-mediated efflux transport at the BBB have been successfully developed in rodents, but it remains unclear whether these can be translated to humans given the pronounced species differences in ABCG2/ABCB1 expression ratios at the BBB. We assessed the efficacy of two different ABCB1/ABCG2 inhibitors to enhance brain distribution of 11C-erlotinib in nonhuman primates as a model of the human BBB. METHODS: Papio anubis baboons underwent PET scans of the brain after intravenous injection of 11C-erlotinib under baseline conditions (n = 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n = 4) or elacridar (12 mg/kg/h, n = 3). RESULTS: Under baseline conditions, 11C-erlotinib distribution to the brain (total volume of distribution [VT], 0.22 ± 0.015 mL/cm3) was markedly lower than its distribution to muscle tissue surrounding the skull (VT, 0.86 ± 0.10 mL/cm3). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in 11C-erlotinib distribution to the brain (VT, 0.81 ± 0.21 mL/cm3, P < 0.01), reaching levels comparable to those in muscle tissue, without changing 11C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (VT, 0.38 ± 0.033 mL/cm3, P < 0.05), with a concomitant increase in 11C-erlotinib plasma exposure. CONCLUSION: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of 11C-erlotinib. For patients with brain tumors, such inhibition protocols may ultimately be applied to create more effective treatments using drugs that undergo efflux transport at the BBB.
Authors: Nicolas Tournier; Sebastien Goutal; Severin Mairinger; Irene Hernández-Lozano; Thomas Filip; Michael Sauberer; Fabien Caillé; Louise Breuil; Johann Stanek; Anna F Freeman; Gaia Novarino; Charles Truillet; Thomas Wanek; Oliver Langer Journal: J Cereb Blood Flow Metab Date: 2020-10-20 Impact factor: 6.200
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Authors: Huanwen Chen; John Kuhn; Kathleen R Lamborn; Lauren E Abrey; Lisa M DeAngelis; Frank Lieberman; H Ian Robins; Susan M Chang; W K Alfred Yung; Jan Drappatz; Minesh P Mehta; Victor A Levin; Kenneth Aldape; Janet E Dancey; John J Wright; Michael D Prados; Timothy F Cloughesy; Patrick Y Wen; Mark R Gilbert Journal: Neurooncol Adv Date: 2020-09-17
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