Prediction of drug-drug interaction potential mediated by transporters between dasatinib and metformin, pravastatin, and rosuvastatin using physiologically based pharmacokinetic modeling

Purpose Recent in vitro studies demonstrated that dasatinib inhibits organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), and organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3). We developed a physiologically based pharmacokinetic (PBPK) model to assess drug-drug interaction (DDI) potential between dasatinib and known substrates for these transporters in a virtual population. Methods The dasatinib PBPK model was constructed using Simcyp (R) Simulator by combining its physicochemical properties, in vitro data, in silico predictions, and pharmacokinetic (PK) results from clinical studies. Model validation against three independent clinical trials not used for model development included dasatinib DDI studies with ketoconazole, rifampin, and simvastatin. The validated model was used to simulate DDIs of dasatinib and known substrates for OCT2 and MATEs (metformin) and OATP1B1/1B3 (pravastatin and rosuvastatin). Results Simulations of metformin PK in the presence and absence of dasatinib, using inhibitor constant (K-i) values measured in vitro, produced estimated geometric mean ratios (GMRs) of the maximum observed concentration (C-max) and area under the concentration-time curve (AUC) of 1.05 and 1.06, respectively. Sensitivity analysis showed metformin exposure increased < 30% in both AUC and C-max when dasatinib K-i was reduced by tenfold for OCT2 and MATEs simultaneously, and <40% with a 20-fold K-i reduction. The estimated GMRs of C-max and AUC for pravastatin and rosuvastatin with co-administration of dasatinib were unity (1.00). Conclusions This PBPK model accurately described the observed PK profiles of dasatinib. The validated PBPK model predicts low risk of clinically significant DDIs between dasatinib and metformin, pravastatin, or rosuvastatin.

Automated summary

This study developed a physiologically based pharmacokinetic model to assess the drug-drug interaction potential between dasatinib and known substrates for transporters. The simulations showed a low risk of clinically significant interactions between dasatinib and metformin, pravastatin, or rosuvastatin.