Boglione-Kerrien C, Picard S, Tron C, Nimubona S, Gangneux J-P, Lalanne S, Lemaitre F, Bellissant E, Verdier M-C, Petitcollin A
Laboratory of Biological Pharmacology, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Centre, Rennes University Hospital, 2 rue Henri le Guilloux, 35033, Rennes, France.
Laboratory of Experimental and Clinical Pharmacology, Faculty of Medicine, Rennes 1 University, Rennes, France.
J Cancer Res Clin Oncol. 2018 Jan;144(1):127-134. doi: 10.1007/s00432-017-2523-2. Epub 2017 Sep 20.
Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies.
Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C ) were assayed by LC-MS/MS. The rates of ADR by quartile of C were compared.
Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C was 1.36 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C were not different.
Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.
泊沙康唑是一种广泛用于预防侵袭性真菌病（IFI）的三唑类抗真菌药物。泊沙康唑片剂比口服混悬液能达到更高的血浆水平，但该制剂在现实生活中的安全性数据较少。本研究旨在评估泊沙康唑片剂在血液系统恶性肿瘤患者中的安全性、药代动力学变异性以及浓度-毒性关系。
前瞻性纳入60例接受泊沙康唑片剂预防IFI治疗的中性粒细胞减少患者。区域药物警戒中心记录并分析药物不良反应（ADR）以评估泊沙康唑的影响。每周采集一次血样，采用液相色谱-串联质谱法（LC-MS/MS）测定血浆谷浓度（C）。比较C四分位数的ADR发生率。
18例患者（30%）发生至少1次归因于泊沙康唑的ADR。20%的患者出现肝功能检查（LFT）异常，导致4例（6.7%）停药。泊沙康唑的中位（范围）C为1.36（<0.1-3.44）μg/mL（患者间CV=43.9%）。随访期间，28.6%的患者至少有1次浓度<0.7μg/mL，35.7%的患者至少有1次浓度>2μg/mL。C四分位数的ADR发生率无差异。
泊沙康唑耐受性良好；然而，LFT异常较为常见。ADR的发生与泊沙康唑暴露无关。由于泊沙康唑浓度高度可变，治疗药物监测（TDM）有助于避免药物暴露不足并提高其预防IFI的疗效。相反，很大一部分患者暴露过度，可能会从剂量减少中获益。
