Prediction of Clinical Transporter Mediated Drug‐Drug Interactions via Co‐measurement of Pitavastatin and Eltrombopag in Human Hepatocyte Models

A structurally identifiable micro-rate constant mechanistic model was used to describe the interaction between pitavastatin and eltrombopag, with improved goodness-of-fit values through co-measurement of pitavastatin and eltrombopag. Transporter association and dissociation rate constants and passive rates out of the cell were similar between pitavastatin and eltrombopag. Translocation into the cell through transporter mediated uptake was six times greater for pitavastatin, leading to pronounced inhibition of pitavastatin uptake by eltrombopag. The passive rate into the cell was 91 times smaller for pitavastatin compared to eltrombopag. A semi-mechanistic PBPK model was developed to evaluate the potential for clinical drug-drug interactions. The PBPK model predicted a two fold increase in the pitavastatin Cmax and AUC in the presence of eltrombopag in simulated healthy volunteers. The use of structural identifiability supporting experimental design, combined with robust micro-rate constant parameter estimates and a semi-mechanistic PBPK model gave more informed predictions of transporter mediated drug-drug interactions.