Strategies to inhibit ABCB1-and ABCG2-mediated efflux transport of Erlotinib at the blood-brain barrier: A PET study on nonhuman primates

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 5 4) and during intravenous infusion of high-dose erlotinib (10 mg/kg/h, n 5 4) or elacridar (12 mg/kg/h, n 5 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 11Cerlotinib 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.