Innovation & Development Laboratory, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Antimicrob Agents Chemother. 2013 Jul;57(7):3147-58. doi: 10.1128/AAC.00281-13. Epub 2013 Apr 29.
New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy.
新型直接作用抗病毒药物（DAAs）可抑制丙型肝炎病毒（HCV）复制，被越来越多地用于治疗慢性丙型肝炎。已发现 DAA 与许多药物类别之间存在明显的药代动力学变异性和高度的药物相互作用潜力。此外，利巴韦林（RBV）常与溶血性贫血相关，通常需要调整剂量，因此在联合抗病毒治疗的患者中提倡进行治疗药物监测（TDM）。然而，由于这些药物之间的极性差异很大，从亲水性（RBV）到高度亲脂性（特拉匹韦[TVR]），同时分析 RBV 和 DAA 构成了分析上的挑战。此外，TVR 在标准十八烷基反相柱色谱上表现出不稳定的行为，必须与其无活性的 C-21 差向异构体代谢物 VRT-127394 分离。我们开发了一种简便的测定法，采用简单的血浆蛋白沉淀，然后通过高效液相色谱-串联质谱（HPLC-MS/MS）同时测定血浆中 RBV、博赛泼维、TVR 及其代谢物 VRT-127394 的水平。这种新的、简单、快速和强大的 HPLC-MS/MS 测定法提供了一种有效的实时 TDM 方法，旨在最大限度地提高疗效，同时最小化抗病毒治疗的毒性。
