Bridging Pharmacokinetics and Pharmacodynamics: A PBPK/PD Model-Based Approach for Deferasirox Dosing in...

Patients with transfusion-dependent thalassemia (TDT) require lifelong blood transfusions, resulting in excessive iron accumulation and necessitating effective chelation therapy. Deferasirox (DFX) is the primary oral iron chelator for managing iron overload; however, the response to this treatment varies substantially within different individuals, potentially because of differences in its pharmacokinetics (PK) and pharmacodynamics (PD). This study aimed to develop a physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) DFX model, integrating hepatic- and transfusion-derived iron burdens to assess their impact on DFX PK and optimize dosing. The model was developed using clinical PK data from Caucasian and Thai populations, comprising healthy individuals and patients with TDT. TDT-specific physiological parameters were incorporated into the TDT model. The verified model was applied to predict the targeted DFX dose required to achieve a 25% reduction in the liver iron concentration (LIC) from baseline after 6 months of treatment based on the baseline LIC and blood transfusion regimen. The model demonstrated high predictive accuracy across populations, identifying the effects of iron levels on DFX clearance. Simulations revealed that patients with higher baseline LIC were more likely to achieve the targeted reduction, whereas those with lower LIC required higher doses because of slower iron mobilization. A reduced blood transfusion regimen was associated with improved therapeutic outcomes at the same DFX dose. The PBPK/PD model proposed targeted DFX doses to achieve a 25% reduction based on baseline LIC levels and transfusion regimen, emphasizing the requirement for individualized dosing strategies based on iron burden and blood transfusion patterns to maximize clinical outcomes.