RT Journal Article SR Electronic T1 Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood–Brain Barrier: A PET Study on Nonhuman Primates JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 117 OP 122 DO 10.2967/jnumed.116.178665 VO 58 IS 1 A1 Nicolas Tournier A1 Sebastien Goutal A1 Sylvain Auvity A1 Alexander Traxl A1 Severin Mairinger A1 Thomas Wanek A1 Ourkia-Badia Helal A1 Irène Buvat A1 Michael Soussan A1 Fabien Caillé A1 Oliver Langer YR 2017 UL http://jnm.snmjournals.org/content/58/1/117.abstract AB 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.