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 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 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, 11 C-erlotinib distribution to the brain (total volume of distribution [V T ], 0.22 6 0.015 mL/cm 3 ) was markedly lower than its distribution to muscle tissue surrounding the skull (V T , 0.86 6 0.10 mL/cm 3 ). Elacridar infusion resulted in a 3.5 6 0.9-fold increase in 11 C-erlotinib distribution to the brain (V T , 0.81 6 0.21 mL/cm 3 , P , 0.01), reaching levels comparable to those in muscle tissue, without changing 11 Cerlotinib plasma pharmacokinetics. During high-dose erlotinib infusion, 11 C-erlotinib brain distribution was also significantly (1.7 6 0.2-fold) increased (V T , 0.38 6 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.

Elucidation of the Impact of P-glycoprotein and Breast Cancer Resistance Protein on the Brain Distribution of Catechol-O-Methyltransferase Inhibitors

“…According to Almeida et al (2013) the maximum concentration obtained in plasma for BIA 9-1079 after a single therapeutic oral dose of 50 mg/person of opicapone was 51 ng/ml, while the IC 50 value herein found was 3.85 mM (approximately 1530 ng/ml). Thus far, the most potent inhibitors capable of affecting efflux at the BBB in humans and nonhuman primates are tariquidar and elacridar (Bauer et al, 2013(Bauer et al, , 2016Montesinos et al, 2014;Tournier et al, 2017); nevertheless, these inhibitors are only available for research. For marketed drugs, modulation of efflux at the BBB is deemed improbable because the unbound systemic concentrations attained at therapeutic doses are low, meaning that major increases in brain uptake are not usually observed in the presence of clinically relevant doses of the inhibitor (Kalvass et al, 2013).…”

A Proof-of-Concept Study to Inhibit ABCG2- and ABCB1-Mediated Efflux Transport at the Human Blood–Brain Barrier

“…In 6 subjects, metabolite data were available for only the 20-and 40-min time points. Because of the low percentage of radiolabeled metabolites in plasma (,10%), total radioactivity counts were considered for construction of an arterial input function, similar to a previous study in which 11 C-erlotinib PET data were modeled in human lung tumors (23). Plasma protein binding of 11 C-erlotinib was determined by incubating plasma samples obtained before each PET scan with 11 C-erlotinib followed by ultrafiltration as described previously (21).…”

“…Erlotinib is a substrate of ABCB1 and ABCG2 with limited brain distribution (17) and was also shown to inhibit ABCG2 and ABCB1 at higher concentrations (14,18). Our recent preclinical data indicated that high-dose intravenous erlotinib administration leads to partial saturation of ABCG2 and ABCB1 transport activity at the BBB, resulting in a nonlinear dose-dependent increase in erlotinib brain distribution (10,11). These data are of considerable interest for a clinical translation, as pulsatile (weekly) supratherapeutic-dose oral erlotinib treatment (up to dosages of 2,550 mg) was shown to be relatively well tolerated in cancer patients and to lead to improved response rates of non-small cell lung cancer brain metastases as compared with standard clinical dosing (19).…”

“…Some multidrug-resistance reversal agents have been repurposed to inhibit ABCB1 and ABCG2 at the human BBB. Promising results have been obtained with tariquidar, which led to up to 5-fold increases in brain distribution of the ABCB1 substrates (R)-11 C-verapamil and 11 C-N-desmethyl-loperamide in healthy human volunteers (7,8). However, at clinically feasible doses, tariquidar inhibits only ABCB1, so that brain uptake of dual ABCB1/ ABCG2 substrates is only marginally increased (9).…”

“…However, at clinically feasible doses, tariquidar inhibits only ABCB1, so that brain uptake of dual ABCB1/ ABCG2 substrates is only marginally increased (9). The dual ABCB1/ABCG2 inhibitor elacridar has shown promise in increasing brain distribution of dual ABCB1/ABCG2 substrates in preclinical species (10,11). However, elacridar was ineffective in humans because of its low oral bioavailability, leading to plasma concentrations far below those required to inhibit ABCB1/ABCG2 at the human BBB (12).…”