DMD #51193 1 In Vitro Characterization of Axitinib Interactions with Human Efflux and Hepatic Uptake Transporters: Implications for Disposition and Drug Interactions

Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1-3. ABC and SLC transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 x 10-6 cm/sec). Active efflux was observed in Caco-2 cells and further evaluation in MDR1-or BCRP-transfected MDCK cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not breast cancer resistance protein (BCRP). Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC 50 values of 3 μ M and 4.4 μ M, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified since an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC 50 for each transporter. However, a GastroPlus TM simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. OATP1B1 and OATP1B3 transfected HEK293 cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [ 14 C]axitinib-equivalents showed rapid absorption and distribution to all tissues except brain. This suggested efflux transport of axitinib may occur at the mouse blood brain barrier. This article has not been copyedited and formatted. The final version may differ from this version.