ArticleCancer chemotherapy and pharmacology2026
Enhancing triapine treatment: strategies for dose optimization and methemoglobin level mitigation.
Article in Cancer chemotherapy and pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
purposeTriapine 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.
methodsA 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.
resultsA 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 mg resulted in exposures matching those observed in nonsmokers.
conclusionThis 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.
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