Purpose <p>Triapine is a potent small-molecule ribonucleotide reductase inhibitor investigated in combination with radiation and/or chemotherapy for the treatment of advanced stage solid cancers. The aim of this study is to develop a population pharmacokinetic-pharmacodynamic (PK/PD) model for triapine to describe the PK parameters, the effect of smoking on exposure, and the relationship between methemoglobin concentrations and exposure.</p> Methods <p>A total of 36 patients with advanced stage cervical or neuroendocrine cancers from two phase I studies were included in the population PK/PD model building. Triapine and methemoblogin plasma concentrations were sampled over an 8-hr or 24-hour period. Data were analyzed by a nonlinear mixed-effects modelling approach. Simulations were performed to optimize the dosing strategy for oral triapine.</p> Results <p>A two-compartment model with two-transit compartment Erlang absorption and first-order elimination best described the PK of triapine, and an effect compartment model best described the PD effect of triapine on methemoglobin concentrations. The final model described triapine PK/PD well, and a 38% increase in triapine clearance was estimated due to smoking. Simulations suggest that dose adjustments may be necessary, as increasing the oral dose for smokers from 100 to 125&#xa0;mg resulted in exposures matching those observed in nonsmokers.</p> Conclusion <p>This study provides a quantitative model characterizing the relationship between triapine exposure and methemoglobin concentrations. The developed PK/PD model can be used to optimize the dosing regimen for oral triapine, illustrating how population PK/PD modeling can inform decision-making throughout the triapine drug development lifecycle.</p>