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

Abstract

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 $\pm$ standard deviations of dose-normalised doxorubicin_{entrapped+free} C_max and AUC_0-∞ were 0.342 $\pm$ 0.134 mg/L and 40.1 $\pm$ 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.

Keywords: Doxorubicin; Liposomes; Nanoparticles; Nonlinear mixed-effects model; Pharmacokinetics; Pharmacometrics.

Fig. 1

Dose-normalised AUC_0-inf (panal a, left) and dose-normalised C_max (panel b, right) vs. individual doses in the two first cycles of the 30 patients treated with TLD-1. AUC_0-inf AUC from t = 0 to infinity; C_max maximum concentration

Fig. 2

Schematic structure of the joint parent-metabolite PK model of entrapped doxorubicin, free doxorubicin and doxorubicinol. Abbreviations: V1: volume of distribution of entrapped doxorubicin; V2: central volume of distribution of free doxorubicin; V3: peripheral volume of distribution of free doxorubicin; V4: volume of distribution of doxorubicinol; CL1: release clearance of the entrapped doxorubicin; CL2: clearance of free doxorubicin for the metabolism to doxorubicinol; CL4: clearance of doxorubicinol; QDoxo,f: intercompartmental clearance between the central and peripheral compartment of free doxorubicin; BSA: body surface area

Fig. 3

Goodness-of-fit plots of (panel a, upper left) population predictions vs. measured concentrations (“observations”) and (panel b, upper right) individual predictions vs. measured concentrations as well as (panel c, lower left) CWRES vs. Time and (panel d, lower right) CWRES vs. population predictions. Blue lines: trend lines. Red points: entrapped doxorubicin. Blue points: free doxorubicin. Purple points: metabolite doxorubicinol. Abbreviations: CWRES: Conditional weighted residuals

Fig. 4

Prediction-corrected visual predictive check for the joint parent-metabolite TLD-1 model characterising entrapped doxorubicin (panel a, upper left), free doxorubicin (panel b, upper right), and doxorubicinol (panel c, lower left). Black solid lines: observed median concentrations; black dashed lines: 10th and 90th percentiles of the observed concentrations; blue solid lines: simulated median concentrations; blue dashed lines: 10th and 90th percentiles of the simulated concentrations; blue shaded areas: 95% confidence intervals around the predicted median concentrations, purple shaded areas: 95% confidence intervals around the 10th and the 90th predicted percentiles, respectively. Black open circles: observed concentrations