Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins

To support drug development, the drug-drug interaction potential (DDI) of an investigational drug (AZX) was assessed against the probe estradiol 17 beta-glucuronide as well as against simvastatin acid, atorvastatin, pravastatin, pitavastatin, fluvastatin, rosuvastatin and estrone 3-sulfate. The inhibitory potentials of the OATP1B1 inhibitors rifamycin SV and gemfibrozil were assessed in parallel. Monolayer cellular uptake assays were used to determine inhibition of human OATP1B1. Apparent K-m values for the OATP1B1-mediated transport of [H-3] substrates were determined prior to their use as probes in inhibition studies, and ranged from 0.6 to 29 mu M for statins. The K-m of lipophilic simvastatin acid could not be determined due to its high passive permeability that masked OATP1B1 transport, and therefore this statin could not be used as a probe. Estrone 3-sulfate exhibited biphasic kinetics, whereas estradiol 17 beta-glucuronide demonstrated simple Michaelis-Menton kinetics. AZX moderately inhibited OATP1B1-mediated transport of all statins (IC50 = 4.6-9.7 mu M), except fluvastatin, of estradiol 17 beta-glucuronide (IC50 = 5.3 mu M), and weakly inhibited estrone 3-sulfate (IC50 = 79 mu M). Rifamycin SV strongly, and gemfibrozil weakly, inhibited the OATP1B1-mediated transport of substrates. Estradiol 17 beta-glucuronide was identified as a good surrogate probe for statins when assessing OATP1B1 inhibitory potential using this test system. Inhibition data was used to predict the likelihood of a clinical DDI, using current draft US FDA guidance and recommendations of the International Transporter Consortium. Predictions for AZX indicated the potential for an OATP1B1-mediated DDI in vivo and that a clinical interaction study is warranted to confirm whether AZX is an OATP1B1 inhibitor in the clinic. (C) 2012 Elsevier B.V. All rights reserved.