Jin Lu

Background: Posaconazole exhibits substantial pharmacokinetic variability, particularly with oral formulations. Real-world data on target attainment across formulations and on specific toxicity thresholds remain limited. This study aimed to evaluate posaconazole target attainment rates, identify independent predictors of subtherapeutic exposure, and explore potential hepatotoxicity exposure thresholds in a real-world Chinese cohort. Methods: This single-centre, retrospective observational study conducted at Nanjing Drum Tower Hospital, China, between January 2023 and August 2025 enrolled 148 patients with IPFI. Posaconazole was administered for prophylaxis with a target trough concentration of ≥ 0.5 mg/L, or for treatment with a target of ≥ 1.0 mg/L. Multivariable logistic regression was utilised to identify independent predictors of subtherapeutic exposure. Results: Subtherapeutic trough concentrations were observed in 24.0% of the prophylaxis group and 23.3% of the treatment group. Concomitant proton pump inhibitor (PPI) use was the dominant independent risk factor for subtherapeutic exposure in both prophylaxis (OR 17.97, 95% CI 4.22– 76.53, P< 0.001) and treatment (OR 3.60, 95% CI 1.10– 11.75, P=0.034) groups. Regarding regimen optimisation, switching to the intravenous formulation proved more effective than oral dose escalation for correcting subtherapeutic levels. Furthermore, an exposure–safety analysis revealed that hepatotoxicity rates increased significantly when trough concentrations exceeded 1.95 mg/L (P=0.015). Conclusion: Subtherapeutic posaconazole exposure remains common. PPI use is a critical risk factor that may not be fully overcome by delayed-release or intravenous formulations. Our findings suggest a potential exposure-hepatotoxicity relationship around 1.95 mg/L for Chinese patients, highlighting the need for individualised TDM.

Disclosure: K.A. de Oliveira: None. F.D. Andrade: None. M. Ozgul-Onal: None. A. Yadav: None. T. Onal: None. L. Jin: None. S. Sengupta: None. R. Clarke: None. Endocrine therapy can lead to cellular nutrient deprivation by reducing glucose and glutamine uptake and total cellular ATP production in breast cancer cells. The ability to bypass this metabolic stress is fundamental to how breast cancer cells regulate growth and acquire endocrine resistance. SIRT3, which can be activated by calorie restriction, modulates mitochondrial adaptation to low energy input. It has a key role in mitochondrial integrity and function, regulating cell survival, death, and metabolism, regulating the shift to amino-acid and fatty-acid catabolism. SIRT3 can maintain ROS levels at the appropriate levels for sustaining a proliferative phenotype, preventing apoptosis and promoting carcinogenesis. A role of SIRT3 in epigenetic regulation has also been reported. The ability of SIRTs to sense and respond to changes in energy, coupled with their intrinsic deacetylase/deacylase functions, could provide a mechanism for the cell to rewire signaling and maintain a newly acquired drug-resistant phenotype. Using antiestrogen sensitive (LCC1) and cross-resistant (LCC9) breast cancer cells, we confirmed higher expression of SIRT3 in LCC9, compared with LCC1 cells. Upregulation of SIRT3 expression within 24 hrs of Fulvestrant (ICI 1 µM) treatment (p=0.0176) in LCC1 was shown, whereas no effect was observed in LCC9 cells. Inhibition of SIRT3 activity, using the inhibitor LC0296 (15 µM), reduced growth rate in both LCC1 and SIRT3-silenced LCC9 cells under treatment with ICI (pPresentation: Thursday, June 15, 2023

Background: This study aimed to investigate the pharmacokinetic/pharmacodynamic (PK/PD) target attainment of various tigecycline dosing regimens in real-world patients with impaired liver function. Methods: The clinical data and serum concentrations of tigecycline were extracted from the patients' electronic medical records. Patients were classified into Child-Pugh A, Child-Pugh B, and Child-Pugh C groups, according to the severity of liver impairment. Furthermore, the minimum inhibition concentration (MIC) distribution and PK/PD targets of tigecycline from the literature were used to obtain a proportion of PK/PD targets attainment of various tigecycline dosing regimens at different infected sites. Results: The pharmacokinetic parameters revealed significantly higher values in moderate and severe liver failure (groups Child-Pugh B and Child-Pugh C) than those in mild impairment (Child-Pugh A). Considering the target area under the time–concentration curve (AUC_0-24)/MIC ≥4.5 for patients with pulmonary infection, most patients with high-dose (100 mg, every 12 hours) or standard-dose (50 mg, every 12 hours) for tigecycline achieved the target in groups Child-Pugh A, B, and C. Considering the target AUC_0-24/MIC ≥6.96 for patients with intra-abdominal infection, when MIC ≤1 mg/L, more than 80% of the patients achieved the target. For an MIC of 2–4 mg/L, only patients with high-dose tigecycline in groups Child-Pugh B and C attained the treatment target. Patients experienced a reduction in fibrinogen values after treatment with tigecycline. In group Child-Pugh C, all 6 patients developed hypofibrinogenemia. Conclusions: Severe hepatic impairment may attain higher PK/PD targets, but carries a high risk of adverse reactions.