Simultaneous Target-Mediated Drug Disposition-Pharmacodynamic Modeling of Finasteride and Dutasteride: Impact of Target Binding and Turnover on Non-Linear Pharmacokinetics

This study developed a physiologically-based pharmacokinetic (PBPK) model incorporating target-mediated drug disposition (TMDD) and pharmacodynamic (PD) responses for finasteride and dutasteride, which are inhibitors of 5α-reductase (5αR). The model effectively captured the non-linear PK and PD profiles of both drugs, showing that saturation of target binding is the main driver of these profiles, while slow turnover of 5αR contributes to prolonged PD effects. The distinct PD profiles of finasteride and dutasteride are due to their differing inhibition characteristics against 5αR subtypes. These findings support the use of TMDD-PD modeling to optimize clinical dosing and improve therapeutic outcomes for small-molecule drugs with time-dependent target inhibition.