Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer

Xu, Gaoqi; Yang, Dihong; He, Chaoneng; Zhong, Like; Zhu, Junfeng; Shen, Qi; Ding, Haiying; Xin, Wenjuan; Tong, Ying; Zhu, Xiao; Fang, Luo

doi:10.1007/s00280-023-04559-y

Cited by 2 publications

(1 citation statement)

References 27 publications

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“…Doxorubicin (DOX) is a classical anthracycline antineoplastic drug that remains widely used and highly effective in the field (G. Xu et al, 2023). Clinical applications and experimental studies of DOX highlight its strong binding ability to phospholipids in the mitochondrial intima and subsequent generation of highly reactive oxygen species upon interaction (Robert Li et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Apigenin alleviates doxorubicin‐induced myocardial pyroptosis by inhibiting glycogen synthase kinase‐3β in vitro and in vivo

Wang,

Yan,

Yue

et al. 2024

Drug Development Research

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Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti‐cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK‐3β and the effects of apigenin in DOX‐induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX‐induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis‐related factors. Furthermore, the phosphorylation of GSK‐3β was enhanced while the phosphorylation of nuclear factor‐kB (NF‐κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA‐GSK‐3β‐transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK‐3β. Therefore, our study confirmed that the inhibition of GSK‐3β and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX‐stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK‐3β expression and subsequent reduction in NF‐κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK‐3β may offer a promising therapeutic approach for alleviating DOX‐induced cardiotoxicity.

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Section: Introductionmentioning

confidence: 99%

Apigenin alleviates doxorubicin‐induced myocardial pyroptosis by inhibiting glycogen synthase kinase‐3β in vitro and in vivo

Wang,

Yan,

Yue

et al. 2024

Drug Development Research

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

Mc Laughlin,

Hess,

Michelet

et al. 2024

Cancer Chemother Pharmacol

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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 doxorubicinentrapped, doxorubicinfree, 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 doxorubicinentrapped+free Cmax and AUC0−∞ 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 (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), 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

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Population pharmacokinetics and toxicity correlation analysis of free and liposome-encapsulated doxorubicin in Chinese patients with advanced breast cancer

Cited by 2 publications

References 27 publications

Apigenin alleviates doxorubicin‐induced myocardial pyroptosis by inhibiting glycogen synthase kinase‐3β in vitro and in vivo

Apigenin alleviates doxorubicin‐induced myocardial pyroptosis by inhibiting glycogen synthase kinase‐3β in vitro and in vivo

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

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