Vethe Nils Tore, Munkhaugen John, Andersen Anders M, Husebye Einar, Bergan Stein
Department of Pharmacology, Oslo University Hospital, Oslo.
Department of Medicine, Drammen Hospital, Vestre Viken Trust, Drammen.
Ther Drug Monit. 2019 Feb;41(1):19-28. doi: 10.1097/FTD.0000000000000578.
Low adherence to statin therapy remains a public health concern associated with poor prognosis in cardiovascular disease patients. A feasible method for statin adherence monitoring in clinical practice has yet to be developed. In this article, we describe a novel method designed for the direct monitoring of atorvastatin adherence based on the sum of parent drug and major metabolites in blood samples.
Acid and lactone forms of atorvastatin, 2-OH-atorvastatin, and 4-OH-atorvastatin were assayed. Plasma proteins were precipitated with an acidified mixture of methanol, acetonitrile, and aqueous zinc sulfate, and the supernatant was analyzed with 2-channel reversed-phase chromatography coupled to tandem mass spectrometry. Assay validation was performed according to the guidelines provided by the European Medicines Agency and the US Food and Drug Administration.
The effective run time was 1 minute and 45 seconds per sample. Mean accuracy ranged from 92% to 110%, and coefficients of variation were ≤8.1% over the measurement ranges for individual compounds. The sum of acids and corresponding lactones was stable in clinical plasma samples kept at ambient temperature for up to 6 days after blood sampling (mean sum within 96.6%-101% of baseline).
A fast and reliable assay for the quantification of atorvastatin and its 5 major metabolites in clinical blood samples is reported. Limitations of preanalytical stability were solved using the sum of the acid and lactone forms. The assay is feasible for implementation in clinical practice, and the sum of parent drug and metabolites may be used for direct monitoring of atorvastatin adherence.
他汀类药物治疗依从性低仍是心血管疾病患者预后不良相关的公共卫生问题。临床实践中尚未开发出一种可行的他汀类药物依从性监测方法。在本文中，我们描述了一种基于血样中母体药物和主要代谢物总和直接监测阿托伐他汀依从性的新方法。
对阿托伐他汀的酸和内酯形式、2-羟基阿托伐他汀和4-羟基阿托伐他汀进行测定。用甲醇、乙腈和硫酸锌水溶液的酸化混合物沉淀血浆蛋白，上清液用双通道反相色谱-串联质谱分析。根据欧洲药品管理局和美国食品药品监督管理局提供的指南进行分析验证。
每个样品的有效运行时间为1分45秒。平均准确度在92%至110%之间，各化合物测量范围内的变异系数≤8.1%。酸和相应内酯的总和在采血后室温下保存长达6天的临床血浆样品中稳定（平均总和在基线的96.6%-101%以内）。
报道了一种快速可靠的临床血样中阿托伐他汀及其5种主要代谢物定量分析方法。利用酸和内酯形式的总和解决了分析前稳定性的局限性。该分析方法在临床实践中可行，母体药物和代谢物的总和可用于直接监测阿托伐他汀的依从性。
