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Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice

Ronilda R D'Cunha1, Daryl J Murry2, Guohua An1

  • 1The Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52246.

Journal of Pharmaceutical Sciences
|June 5, 2019
PubMed

Insights

Nilotinib effectively inhibits efflux transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), overcoming TKI resistance. Coadministration with nilotinib significantly enhances afatinib

Area of Science:

  • Pharmacology
  • Oncology
  • Drug Discovery

Background:

  • Small-molecule tyrosine kinase inhibitors (TKIs) offer improved selectivity and safety over traditional chemotherapy.
  • Acquired resistance, often due to efflux transporter overexpression (P-glycoprotein [Pgp], breast cancer resistance protein [BCRP]), limits TKI efficacy.
  • TKIs can act as both substrates and inhibitors of Pgp and BCRP, suggesting combination therapy potential.

Purpose of the Study:

  • To investigate the in vitro effects of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux.
  • To evaluate the pharmacokinetic impact of combining nilotinib with afatinib in vivo.

Main Methods:

  • In vitro assessment of 14 TKIs' inhibition of Pgp, Bcrp1, and BCRP.
  • Determination of afatinib pharmacokinetics in mice plasma and tissues with and without nilotinib coadministration.

Main Results:

  • Nilotinib demonstrated potent inhibition of Pgp (EC50=2.22 μM), Bcrp1 (EC50=2.47 μM), and BCRP (EC50=0.692 μM).
  • Coadministration of nilotinib increased afatinib area under the curve (AUC) by 188% in plasma and altered tissue AUC.
  • Nilotinib reduced afatinib clearance by 65.3%.

Conclusions:

  • Nilotinib is a potent inhibitor of key drug efflux transporters implicated in TKI resistance.
  • Nilotinib significantly alters afatinib pharmacokinetics, suggesting potential to overcome transporter-mediated resistance.
  • Further investigation in tumor models is warranted to confirm nilotinib's chemosensitizing effects.
Keywords:
P-glycoproteinbreast cancer resistance proteincombination therapyefflux pumpspharmacokineticstyrosine kinase inhibitors

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