Physiologically based pharmacokinetic modeling of tafenoquine and evaluation of transporter-mediated drug–drug interactions

Introduction: malaria and assess drug-drug interactions with substrates of the transporters OCT2 and MATE1. Methods: A whole-body PBPK model was built using PK-Sim® to simulate 100 adults aged 19-53 years weighing 51-108 kg. Hepatic clearance was incorporated into the model. Literature data on the oral administration of TQ were used to verify the model. The qualified model was used to simulate co-administration with metformin (MTF), an OCT2 and MATE1 substrate, and assess drug-drug interactions. Results and Discussion: The PBPK model presented a good descriptive and predictive performance for plasma concentration-time profiles. Quantitative measures of the model performance fell within the 2-fold acceptance criteria when predictions were compared to observed values. Co-administration of TQ with MTF presented no alteration of MTF's exposure. Model simulations suggest that there is no significant interaction between TQ and substrates of OCT2/MATE1, such as MTF.