Dolton Michael J, Brüggemann Roger J M, Burger David M, McLachlan Andrew J
Faculty of Pharmacy, University of Sydney, Camperdown, Australia Centre For Education and Research on Ageing, Concord Repatriation General Hospital, Concord, Australia.
Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Antimicrob Agents Chemother. 2014 Nov;58(11):6879-85. doi: 10.1128/AAC.03777-14. Epub 2014 Sep 8.
Posaconazole oral suspension is widely used for antifungal prophylaxis and treatment in immunocompromised patients, with highly variable pharmacokinetics reported in patients due to inconsistent oral absorption. This study aimed to characterize the pharmacokinetics of posaconazole in adults and investigate factors that influence posaconazole pharmacokinetics byusing a population pharmacokinetic approach. Nonlinear mixed-effects modeling was undertaken for two posaconazole studies in patients and healthy volunteers. The influences of demographic and clinical characteristics, such as mucositis, diarrhea, and drug-drug interactions, on posaconazole pharmacokinetics were investigated using a stepwise forward inclusion/backwards deletion procedure. A total of 905 posaconazole concentration measurements from 102 participants were analyzed. A one-compartment pharmacokinetic model with first-order oral absorption with lag time and first-order elimination best described posaconazole pharmacokinetics. Posaconazole relative bioavailability was 55% lower in patients who received posaconazole than in healthy volunteers. Coadministration of proton pump inhibitors (PPIs) or metoclopramide, as well as the occurrence of mucositis or diarrhea, reduced posaconazole relative bioavailability by 45%, 35%, 58%, and 45%, respectively, whereas concomitant ingestion of a nutritional supplement significantly increased bioavailability (129% relative increase). Coadministration of rifampin or phenytoin increased apparent posaconazole clearance by more than 600%, with a smaller increase observed with fosamprenavir (34%). Participant age, weight, or sex did not significantly affect posaconazole pharmacokinetics. Posaconazole absorption was reduced by a range of commonly coadministered medicines and clinical complications, such as mucositis and diarrhea. Avoidance of PPIs and metoclopramide and administration with food or a nutritional supplement are effective strategies to increase posaconazole absorption.
泊沙康唑口服混悬液广泛用于免疫功能低下患者的抗真菌预防和治疗，由于口服吸收不一致，患者体内的药代动力学差异很大。本研究旨在通过群体药代动力学方法描述成人泊沙康唑的药代动力学特征，并研究影响泊沙康唑药代动力学的因素。对两项针对患者和健康志愿者的泊沙康唑研究进行了非线性混合效应建模。使用逐步向前纳入/向后删除程序，研究了人口统计学和临床特征（如粘膜炎、腹泻和药物相互作用）对泊沙康唑药代动力学的影响。共分析了102名参与者的905次泊沙康唑浓度测量值。具有滞后时间的一级口服吸收和一级消除的单室药代动力学模型最能描述泊沙康唑的药代动力学。接受泊沙康唑治疗的患者中，泊沙康唑的相对生物利用度比健康志愿者低55%。同时服用质子泵抑制剂（PPI）或甲氧氯普胺，以及发生粘膜炎或腹泻，分别使泊沙康唑的相对生物利用度降低45%、35%、58%和45%，而同时摄入营养补充剂则显著提高生物利用度（相对增加129%）。同时服用利福平或苯妥英钠可使泊沙康唑的表观清除率增加600%以上，福沙那韦的增加幅度较小（34%）。参与者的年龄、体重或性别对泊沙康唑的药代动力学没有显著影响。一系列常用的联合用药和临床并发症（如粘膜炎和腹泻）会降低泊沙康唑的吸收。避免使用PPI和甲氧氯普胺，并与食物或营养补充剂一起服用是增加泊沙康唑吸收的有效策略。
