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The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4. Furthermore, a joint parent-metabolite PK model of doxorubicin entrapped , doxorubicin free , and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored.
The median half-life 95 h was The novel joint parent-metabolite model comprised a one-compartment model with linear release doxorubicin entrapped , a two-compartment model with linear elimination doxorubicin free , and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate. The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses.
Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies.
The mechanism of action of this anthracycline is a combination of free radical formation, cellular membrane interaction, topoisomerase II inhibition, and DNA intercalation, all ultimately leading to apoptosis [ 1 , 3 , 4 ].
