High dose erlotinib as an alternative to elacridar for the combined inhibition of ABCB1 and ABCG2 at the blood-brain barrier: an 11C-erlotinib PET study in nonhuman primates

1813 Objectives Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are two major efflux transporters expressed at the blood-brain barrier (BBB) that work together to restrict brain distribution of dual ABCG2/ABCB1 substrate drugs such as tyrosine kinase inhibitors (TKIs) like erlotinib. ABCG2/ABCB1-mediated efflux at the BBB is therefore a major impediment for the treatment of brain tumors and metastases with erlotinib or other TKIs. Pharmacological protocols for combined inhibition of ABCG2/ABCB1-mediated efflux at the BBB have been successfully developed in rodents. However, as ABCG2/ABCB1 expression ratios at the BBB are fundamentally different between rodents (Abcg2/Abcb1a: 0.3) and humans/nonhuman primates (ABCG2/ABCB1: 1.3) a direct translation of transporter inhibition protocols from rodents to humans may be difficult. In this study we assessed the effect of two different ABCB1/ABCG2 inhibitors (elacridar and high dose erlotinib) on brain distribution of 11C-erlotinib in nonhuman primates. Methods 11C-erlotinib PET imaging and measurement of a metabolite-corrected arterial input function were performed in three baboons to estimate 11C-erlotinib volume of distribution (VT, mL.cm-3) in the brain and temporal muscles surrounding the skull using Logan Plot analysis. PET experiments were performed i) under baseline conditions, ii) during high dose erlotinib infusion (10 mg/kg/h) and iii) during infusion of the potent ABCG2/ABCB1 inhibitor elacridar (12 mg/kg/h) (n=3 for each condition). Elacridar and erlotinib concentrations in plasma at the time of 11C-erlotinib injection were determined with HPLC analysis. Results 11C-erlotinib baseline brain VT was low (0.18±0.10) and was significantly increased using high dose erlotinib (0.33±0.03) or elacridar (0.70±0.35). 11C-erlotinib brain VTs were not significantly different between high dose erlotinib and elacridar administration. Muscle VTs were not significantly different between baseline condition (0.88±0.07), high dose erlotinib (0.98±0.02) and elacridar (0.85±0.11). Plasma concentrations of erlotinib (17.5 ± 0.8 µM) and elacridar (16.6 ± 3.3 µM) were similar at the time of PET. Conclusions We showed for the first time in nonhuman primates, a relevant animal model of the human BBB, that substantial ABCG2/ABCB1 inhibition at the BBB can be achieved using elacridar infusion resulting in markedly improved brain delivery of the ABCB1/ABCG2 substrate 11C-erlotinib. We also demonstrated that high dose erlotinib significantly enhanced brain delivery of 11C-erlotinib, most likely through the saturation of transporter function at the BBB. High dose erlotinib infusion may thus offer a promising alternative to dedicated inhibitors such elacridar, which are not readily available for human use, to improve brain delivery of dual ABCB1/ABCG2 substrate drugs in patients. $$graphic_74AA1962-874D-4789-BC07-1E4DE35DD0BF$$