Bypassing P-glycoprotein mediated efflux of afatinib by cyclodextrin complexation - Evaluation of intestinal absorption and anti-cancer activity

A cyclodextrin complex of afatinib, a FDA-approved pan-ErbB inhibitor and known P-gp substrate, was developed to enhance its bio-activity while also reducing p-glycoprotein (P-gp) efflux, thereby improving its transport across the intestinal membrane. A sulfobutyl ether derivative of beta-cyclodextrin (SBE-beta-CD, pharmaceutical grade) was selected based on preliminary phase solubility studies and molecular modeling to prepare an afatinib-cyclodextrin inclusion complex. Various solid-state characterization studies were performed to confirm complex formation and to evaluate its physicochemical properties. Results showed that complexation with SBE-beta-CD enhanced afatinib's stability in PBS (pH 7.4), as well as in simulated gastric (pH 2.0) and intestinal fluids (pH 6.5). In addition, the cytotoxicity (reduced IC50 after complexation acrossmultiple cancer cell lines with varied P-gp expression) and tumor volume retraction ability (in-vitro 3D-spheroids of P-gp overexpressing cell lines) of afatinib were both enhanced through cyclodextrin complexation. CD complexation effect of afatinib on P-gp efflux as well as transport was assessed using in-vitro permeability studies (Caco-2 and EpiIntestinal (R) tissue models). Results demonstrated that cyclodextrin complexation significantly increased the transport of afatinib across the gut membrane while also reducing its efflux ratio, indicating its vital role in P-gp efflux modulation. (C) 2020 Elsevier B.V. All rights reserved.

Automated summary

A cyclodextrin complex of afatinib was developed to enhance its bio-activity and stability, reduce P-gp efflux, and improve its transport across the intestinal membrane. Various studies confirmed the complex formation and physicochemical properties. The complexation significantly increased transport of afatinib across the gut membrane while reducing its efflux ratio, demonstrating its vital role in P-gp efflux modulation.