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首页> 外文期刊>Journal of mass spectrometry: JMS >Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV
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Development and validation of a multiplex UHPLC-MS/MS assay with stable isotopic internal standards for the monitoring of the plasma concentrations of the antiretroviral drugs bictegravir, cabotegravir, doravirine, and rilpivirine in people living with HIV

机译：多重UHPLC-MS / MS测定的开发和验证具有稳定的同位素内部标准，用于监测抗逆转录虫药物Bictegravir，Cabotegravir，Doravirine和艾滋病病毒症的人们的血浆浓度

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The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs.
机译：高度活跃的抗逆转录病毒治疗的广泛使用大大改变了艾滋病毒（PLWH）的人们的预后。然而，必须在维持治疗效果和长期耐受性的情况下终身提高这种治疗。最近批准或研究抗逆转录病毒药物具有相当大的优点，允许每日口服剂量以及抗抗性变体（例如，Bictegravir和Doravirine）的活性，以及​​促进治疗粘附的肠胃外颗粒局（例如，长效注射制剂如Cabotegravir和Rilpivirine ）。尽管如此，由于吸收问题，异常消除，药物 - 药物相互作用等，仍然存在不足或夸张的循环暴露的风险。在这种情况下，已经开发了与串联质谱（UHPLC-MS / MS）生物测定的多重超高效液相色谱法，用于监测PLWH中的Bictegravir，Cabothgir，Doravirine和柠檬水的血浆水平。进行简单方便的蛋白质沉淀，然后将上清液直接注射到UHPLC-MS / MS系统中。使用与三重四极杆质谱检测耦合的反相色谱法，在不到3分钟内洗脱四种分析物。在国际指南下，此类生物测定是完全验证的，在临床相关浓度范围内（3.0％-11％），可重复性（2.6％-11％）和中间精度（3.0％-11.2％）取得了良好的性能对于Bictegravir，Cabotegravir和Doravirine的30至9000 ng / ml，瑞培的10至1800ng / ml）。这种敏感的，准确和快速的UHPLC-MS / MS测定目前在我们的常规治疗药物监测中应用了口腔药物Bictegravir和Doravirine的实验室，并且还旨在用于从PLWH的血浆中的Cabotegravir / Rilpivirine水平的监测每月接受一次或每2个月内肌肉注射这些长效抗逆转录病毒药物。

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