Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, 6 Święcickiego Street, 60-781 Poznań, Poland.
J Pharm Biomed Anal. 2018 May 10;153:199-203. doi: 10.1016/j.jpba.2018.02.049. Epub 2018 Feb 24.
Currently, there is an urgent need to establish the optimal dosing of TREO in conditioning prior to hematopoietic stem cell transplantation, especially in children. For that purpose, pharmacokinetic analyses are ongoing within clinical phase II and III trials. In this paper, HPLC methods for determination of prodrug treosulfan and/or its biologically active epoxides in human plasma or serum are reviewed for the first time, including the spectrum of analytes being quantified, detection type, and derivatization methodology. The major focus is addressed to the stability of TREO and its monoepoxide related with different strategies of patients' blood processing, e.g. blood pH lowering to different values, no pH adjustment; centrifugation of blood immediately after collection or within a few hours later. This issue is crucially important for the robust bioanalysis because the epoxytransformation of TREO is a nonenzymatic, highly pH and temperature-dependent reaction. In-depth analysis of the literature results demonstrates that some methodologies of blood treatment could produce the systematic underestimation of TREO concentrations. Consequently, the drug clearance and volume of distribution will be overestimated, which might false the association of the drug exposure with the regimen-related toxicity and clinical outcomes. The paper indicates the deficiencies of the blood processing strategies and offers hints for their refinement. The provided information ought to be important in the current investigations of the personalized TREO pharmacokinetics.
目前，在进行造血干细胞移植前的预处理时，迫切需要确定 TREO 的最佳剂量，特别是在儿童中。为此，正在进行临床 II 期和 III 期试验中的药代动力学分析。本文首次综述了用于测定人血浆或血清中前药 treosulfan 和/或其生物活性环氧化物的 HPLC 方法，包括定量分析物的范围、检测类型和衍生化方法。主要关注的是 TREO 及其单环氧物的稳定性，以及与患者血液处理的不同策略相关，例如将血液 pH 值降低到不同的值、不进行 pH 值调整；采血后立即或数小时后进行离心。对于稳健的生物分析来说，这个问题至关重要，因为 TREO 的环氧化转化是非酶促的，高度依赖 pH 值和温度。对文献结果的深入分析表明，某些血液处理方法可能会导致 TREO 浓度的系统低估。因此，药物清除率和分布容积将被高估，这可能会错误地将药物暴露与方案相关毒性和临床结果联系起来。本文指出了血液处理策略的缺陷，并为其改进提供了线索。提供的信息在当前的 TREO 个体化药代动力学研究中应该是重要的。
