Faculty of Pharmacy, University of Sydney, Sydney, Australia.
Antimicrob Agents Chemother. 2012 Nov;56(11):5503-10. doi: 10.1128/AAC.00802-12. Epub 2012 Aug 13.
Posaconazole has an important role in the prophylaxis and salvage treatment of invasive fungal infections (IFIs), although poor and variable bioavailability remains an important clinical concern. Therapeutic drug monitoring of posaconazole concentrations has remained contentious, with the use of relatively small patient cohorts in previous studies hindering the assessment of exposure-response relationships. This multicenter retrospective study aimed to investigate relationships between posaconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect posaconazole concentrations. Medical records were reviewed for patients who received posaconazole and had ≥1 concentration measured at six hospitals in Australia. Data from 86 patients with 541 posaconazole concentrations were included in the study. Among 72 patients taking posaconazole for prophylaxis against IFIs, 12 patients (17%) developed a breakthrough fungal infection; median posaconazole concentrations were significantly lower than in those who did not develop fungal infection (median [range], 289 [50 to 471] ng/ml versus 485 [0 to 2,035] ng/ml; P < 0.01). The median posaconazole concentration was a significant predictor of breakthrough fungal infection via binary logistic regression (P < 0.05). A multiple linear regression analysis identified a number of significant drug interactions associated with reduced posaconazole exposure, including coadministration with proton pump inhibitors, metoclopramide, phenytoin or rifampin, and the H(2) antagonist ranitidine (P < 0.01). Clinical factors such as mucositis, diarrhea, and the early posttransplant period in hematopoietic stem cell transplant recipients were also associated with reduced posaconazole exposure (P < 0.01). Low posaconazole concentrations are common and are associated with breakthrough fungal infection, supporting the utility of monitoring posaconazole concentrations to ensure optimal systemic exposure.
泊沙康唑在侵袭性真菌感染（IFI）的预防和挽救治疗中具有重要作用，尽管其生物利用度较差且变化较大仍然是一个重要的临床关注点。泊沙康唑浓度的治疗药物监测一直存在争议，以前的研究中使用的患者队列相对较小，这阻碍了对暴露-反应关系的评估。这项多中心回顾性研究旨在调查泊沙康唑浓度与临床结局和不良事件之间的关系，并评估可能影响泊沙康唑浓度的临床因素和药物相互作用。对在澳大利亚六家医院接受泊沙康唑治疗且至少有 1 次浓度检测的患者的病历进行了回顾。本研究纳入了 86 例患者的 541 次泊沙康唑浓度数据。在 72 例接受泊沙康唑预防 IFI 的患者中，有 12 例（17%）发生突破性真菌感染；发生真菌感染的患者的泊沙康唑浓度中位数显著低于未发生真菌感染的患者（中位数[范围]，289[50 至 471]ng/ml 比 485[0 至 2,035]ng/ml；P<0.01）。通过二项逻辑回归分析，泊沙康唑浓度中位数是预测突破性真菌感染的一个显著指标（P<0.05）。多元线性回归分析确定了一些与降低泊沙康唑暴露相关的显著药物相互作用，包括与质子泵抑制剂、甲氧氯普胺、苯妥英或利福平以及 H2 拮抗剂雷尼替丁的联合用药（P<0.01）。临床因素如粘膜炎、腹泻以及造血干细胞移植受者的移植后早期也与降低泊沙康唑暴露有关（P<0.01）。低泊沙康唑浓度很常见，并且与突破性真菌感染有关，支持监测泊沙康唑浓度以确保最佳全身暴露的实用性。
