Risk Factors for Subtherapeutic Exposure and Hepatotoxicity Threshold of Posaconazole: A Real-World Study in Chinese Patients with Invasive Pulmonary Fungal Infection

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Abstract
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.

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