Strategies to Inhibit ABCB1- and ABCG2-Mediated Efflux Transport of Erlotinib at the Blood-Brain Barrier: A PET Study on Nonhuman Primates.

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 ¹¹ C-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 ¹¹ C-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, ¹¹ C-erlotinib distribution to the brain (total volume of distribution [V _T ], 0.22 ± 0.015 mL/cm ³ ) was markedly lower than its distribution to muscle tissue surrounding the skull (V _T , 0.86 ± 0.10 mL/cm ³ ). Elacridar infusion resulted in a 3.5 ± 0.9-fold increase in ¹¹ C-erlotinib distribution to the brain (V _T , 0.81 ± 0.21 mL/cm ³ , P < 0.01), reaching levels comparable to those in muscle tissue, without changing ¹¹ C-erlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, ¹¹ C-erlotinib brain distribution was also significantly (1.7 ± 0.2-fold) increased (V _T , 0.38 ± 0.033 mL/cm ³ , P < 0.05), with a concomitant increase in ¹¹ C-erlotinib plasma exposure.
Conclusion: We successfully implemented ABCB1/ABCG2 inhibition protocols in nonhuman primates resulting in pronounced increases in brain distribution of ¹¹ C-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.
(© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)