Simultaneous Target-Mediated Drug Disposition-Pharmacodynamic (TMDD-PD) Modeling of Finasteride and Dutasteride: Impact of Target Binding and Turnover on Non-linear Pharmacokinetics.

Target-mediated drug disposition (TMDD) refers to non-linear pharmacokinetic (PK) profiles arising from the saturable interaction between a drug and its pharmacological target. Recently, our group revisited the TMDD cases observed in small-molecule drugs interacting with high-specificity targets, obtaining quantitative insights into in vivo target binding. In this study, we developed a physiologically-based PK (PBPK) model incorporating TMDD and pharmacodynamic (PD) responses (TMDD-PD) for finasteride and dutasteride, two time-dependent inhibitors of 5α-reductase (5αR). In addition to the tissue- and subtype-dependent 5αR inhibition, the model incorporated irreversible inactivation of 5αR and its turnover to account for the mechanism of time-dependent inhibition. We simultaneously analyzed the non-linear PK and PD (dihydrotestosterone level decline and recovery) data for both finasteride and dutasteride. Our model effectively captured the observed PK/PD profiles of both drugs, and the model-derived 5αR inhibition parameters were comparable to those obtained from in vitro 5αR inhibition data. Sensitivity analysis revealed that saturation of target binding is the primary driver of the non-linear PK and corresponding PD profiles, while slow turnover of 5αR contributes to the prolonged PD effect. Our results further suggest that the distinct PD profiles of finasteride and dutasteride are attributable to their differing inhibition characteristics against 5αR subtypes (selectivity and affinity). These findings extend our previous work and further support the utility of TMDD-PD modeling for optimizing clinical dose and improving therapeutic outcomes for small-molecule drugs exhibiting TMDD with time-dependent target inhibition.