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

J Nucl Med. 2017 Jan;58(1):117-122. doi: 10.2967/jnumed.116.178665. Epub 2016 Aug 4.

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 = 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.

Keywords: P-glycoprotein; blood–brain barrier; brain metastasis; breast cancer resistance protein; erlotinib.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism*
  • Acridines / administration & dosage*
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / metabolism*
  • Dose-Response Relationship, Drug
  • Erlotinib Hydrochloride / administration & dosage
  • Erlotinib Hydrochloride / pharmacokinetics*
  • Male
  • Molecular Imaging / methods*
  • Papio anubis
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Transport / drug effects
  • Protein Transport / physiology
  • Radiopharmaceuticals / administration & dosage
  • Radiopharmaceuticals / pharmacokinetics
  • Tetrahydroisoquinolines / administration & dosage*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Acridines
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Radiopharmaceuticals
  • Tetrahydroisoquinolines
  • Erlotinib Hydrochloride
  • Elacridar