Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial

Study objectives TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1’s population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling. Methods 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 4.5-fold dose range. 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. Results Medians ± standard deviations of dose-normalised doxorubicin entrapped+free C max and AUC 0−∞ were 0.342 ± 0.134 mg/L and 40.1 ± 18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. 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. Conclusion 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. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies. Clinical trial registration ClinicalTrials.gov–NCT03387917–January 2, 2018