Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Switzerland.
Service of Infectious Diseases, Lausanne University Hospital and University of Lausanne, Switzerland.
J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Sep 1;1125:121733. doi: 10.1016/j.jchromb.2019.121733. Epub 2019 Jul 25.
Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.
由于高效抗逆转录病毒治疗，HIV 感染现在被认为是一种慢性疾病。因此，HIV 感染者（PLWH）寿命更长，并且会遇到更多与年龄相关的慢性合并症，特别是心血管疾病，导致多种药物治疗。由于药物-药物相互作用（DDI）的管理是 PLWH 护理的关键方面，因此需要更彻底地描述心血管和抗 HIV 药物之间的药代动力学 DDI 的程度。为此，开发了一种 UHPLC-MS/MS 生物分析方法，用于同时测定人血浆中的氨氯地平、美托洛尔、普伐他汀、罗苏伐他汀、阿托伐他汀及其活性代谢物。用甲醇对血浆样品进行蛋白沉淀，然后在室温下氮气中蒸发上清液，使可测量的血浆浓度达到亚纳克/毫升以下水平。使用稳定同位素标记的分析物作为内标。使用 6 分钟的液相色谱运行，结合电喷雾三重四极杆质谱检测，分析五种药物和两种代谢物。该方法在临床上相关的浓度范围内进行了验证，范围为氨氯地平、阿托伐他汀和 p-OH-阿托伐他汀为 0.3 至 480ng/mL，普伐他汀为 0.4 至 480ng/mL，罗苏伐他汀和 o-OH-阿托伐他汀为 0.5 至 480ng/mL，美托洛尔为 3 至 4800ng/mL。准确度（95.4-110.8%）、重复性（1.5-13.4%）和中间精密度（3.6-14.5%）等验证性能符合当前国际建议。准确度谱（总误差方法）在生物分析中可接受的±30%范围内。这种快速而稳健的 UHPLC-MS/MS 测定法可同时定量测定血浆中主要的当前使用的心血管药物，并为临床药代动力学和 DDI 研究提供有效的分析工具。
