American Health Sciences, San Francisco, California, USA.
Antimicrob Agents Chemother. 2010 Sep;54(9):3609-13. doi: 10.1128/AAC.01396-09. Epub 2010 Jun 1.
This prospective study evaluated the plasma and intrapulmonary pharmacokinetics and pharmacodynamics (PKPD) of posaconazole (POS) in lung transplant recipients. Twenty adult lung transplant patients were instructed to take a 400-mg POS oral suspension twice daily (BID) with a high-fat meal for a total of 14 doses. Pulmonary epithelial lining fluid (ELF) and alveolar cell (AC) samples were obtained via bronchoalveolar lavage, and blood samples were collected at the approximate time of bronchoscopy. POS concentrations were assayed using liquid chromatography with tandem mass spectrometry. The maximum concentrations (C(max)) (mean +/- standard deviation [SD]) in plasma, ELF, and AC were 1.3 +/- 0.4, 1.3 +/- 1.7, and 55.4 +/- 44.0 microg/ml. POS concentrations in plasma, ELF, and AC did not decrease significantly, indicating slow elimination after multiple dosing. Mean concentrations of POS in plasma, ELF, and AC were above the MIC(90) (0.5 microg/ml) for Aspergillus species over the 12-h dosing interval and for 24 h following the last dose. Area under the concentration-time curve from 0 to 12 h (AUC(0-12))/MIC(90) ratios in plasma, ELF, and AC were 21.98, 22.42, and 1,060. We concluded that a dose of 400 mg BID resulted in sustained plasma, ELF, and AC concentrations above the MIC(90) for Aspergillus spp. during the dosing interval. Confirmation of the therapeutic value of these observations requires further investigation. The intrapulmonary PKPD of POS may be favorable for treatment or prevention of aspergillosis, although further research on the relevant PKPD parameters and the effect of POS protein binding is required.
本前瞻性研究评估了泊沙康唑（POS）在肺移植受者中的血浆和肺内药代动力学和药效学（PKPD）。20 名成年肺移植患者被指示在高脂肪餐后每天两次（BID）服用 400mg POS 口服混悬剂，共服用 14 剂。通过支气管肺泡灌洗获得肺上皮衬液（ELF）和肺泡细胞（AC）样本，并在支气管镜检查时采集血样。使用液质联用色谱法测定 POS 浓度。血浆、ELF 和 AC 中的最大浓度（C(max)）（平均值±标准偏差[SD]）分别为 1.3±0.4、1.3±1.7 和 55.4±44.0μg/ml。多次给药后，POS 血浆、ELF 和 AC 浓度无明显下降，表明其消除缓慢。在 12 小时给药间隔内，POS 血浆、ELF 和 AC 的平均浓度均高于曲霉菌种的 MIC(90)（0.5μg/ml），且在最后一次给药后 24 小时内均高于 MIC(90)。血浆、ELF 和 AC 中的 AUC(0-12)/MIC(90)比值分别为 21.98、22.42 和 1060。我们得出结论，每日 400mg BID 剂量可使 POS 血浆、ELF 和 AC 浓度在给药间隔内持续高于曲霉菌种的 MIC(90)。这些观察结果的治疗价值需要进一步研究证实。POS 的肺内 PKPD 可能有利于曲霉菌病的治疗或预防，尽管需要进一步研究相关 PKPD 参数和 POS 蛋白结合的影响。
