Introduction Further optimization of therapeutic drug monitoring (TDM) for aminoglycosides (AGs) is urgently needed, especially in special populations such as those with cystic fibrosis (CF), >50% of whom develop ototoxicity if treated with multiple courses of IV AGs. This study aimed to empirically test a pharmacokinetic (PK) model using Bayesian estimation of drug exposure in the deeper body tissues to determine feasibility for prediction of ototoxicity. Materials and methods IV doses (n = 3645) of tobramycin and vancomycin were documented with precise timing from 38 patients with CF (aged 8–21 years), including total doses given and total exposure (cumulative AUC). Concentration results were obtained at 3 and 10 h for the central (C1) compartment. These variables were used in Bayesian estimation to predict trough levels in the secondary tissue compartments (C2 trough) and maximum concentrations (C2max). The C1 and C2 measures were then correlated with hearing levels in the extended high-frequency range. Results Patients with more severe hearing loss were older and had a higher number of tobramycin C2max concentrations >2 mg/L than patients with normal or lesser degrees of hearing loss. These two factors together significantly predicted average high-frequency hearing level (r = 0.618, P < 0.001). Traditional metrics such as C1 trough concentrations were not predictive. The relative risk for hearing loss was 5.8 times greater with six or more tobramycin courses that exceeded C2max concentrations of 3 mg/L or higher, with sensitivity of 83% and specificity of 86%. Conclusions Advanced PK model-informed analysis predicted ototoxicity risk in patients with CF treated with tobramycin and demonstrated high test prediction.

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药代动力学模型预测静脉注射妥布霉素治疗囊性纤维化的耳毒性风险

简介 迫切需要进一步优化氨基糖苷类 (AG) 的治疗药物监测 (TDM)，尤其是在特殊人群中，例如囊性纤维化 (CF) 患者，如果接受多个疗程的 IV AG 治疗，其中 >50% 的患者会出现耳毒性。本研究旨在通过使用贝叶斯估计在更深的身体组织中的药物暴露来经验性地测试药代动力学 (PK) 模型，以确定预测耳毒性的可行性。材料和方法 妥布霉素和万古霉素的 IV 剂量 (n = 3645) 记录了来自 38 名 CF 患者（年龄 8-21 岁）的精确时间，包括给予的总剂量和总暴露量（累积 AUC）。中央 (C1) 隔室在 3 和 10 小时时获得浓度结果。这些变量用于贝叶斯估计，以预测次级组织隔室中的谷水平（C2 谷）和最大浓度（C2max）。然后将 C1 和 C2 测量与扩展高频范围内的听力水平相关联。结果 与听力损失正常或程度较轻的患者相比，听力损失更严重的患者年龄更大，妥布霉素 C2max 浓度＞2 mg/L 的数量更多。这两个因素一起显着预测了平均高频听力水平（r = 0.618，P < 0.001）。C1 谷浓度等传统指标无法预测。使用超过 3 mg/L 或更高 C2max 浓度的 6 个或更多妥布霉素疗程，听力损失的相对风险增加 5.8 倍，敏感性为 83%，特异性为 86%。