Bayer AG, Research & Development, Pharmaceuticals, Drug Metabolism and Pharmacokinetics, Wuppertal, Germany.
Chrestos Concept GmbH & Co. KG, Essen, Germany.
J Chromatogr B Analyt Technol Biomed Life Sci. 2021 May 15;1172:122643. doi: 10.1016/j.jchromb.2021.122643. Epub 2021 Mar 5.
A straightforward and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay allowing the sensitive and selective quantitation of finerenone (BAY 94-8862) in lithium heparin human plasma is described. Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that is in phase III clinical trials for the treatment of chronic kidney disease. Finerenone quantitation is performed after addition of its stable isotope-labelled internal standard (ISTD) by protein precipitation with acidified acetonitrile followed by HPLC-MS/MS separation and detection. The determination of finerenone concentrations was validated for a plasma volume of 0.100 mL and subsequently also for a lower plasma volume of 0.010 mL, collected e.g. in paediatric studies. The analytical range was from 0.100 µg/L (lower limit of quantification) to 200 µg/L (upper limit of quantification). Inter-day accuracy was 99.7-105.0% for the plasma volume of 0.100 mL and 101.1-104.5% for the plasma volume of 0.010 mL. Inter-day precision was ≤ 7.0%, independent of the extracted plasma volume. A moderate, concentration-independent matrix effect on ionisation was observed for both finerenone and its ISTD of 0.535-0.617, which is fully compensated by the ISTD (ISTD-normalised matrix factors were 0.98-1.03). The assay was successfully applied with both validated plasma volumes to a clinical phase I study in which the pharmacokinetics of 20 mg finerenone were compared in capillary plasma (0.010 mL) and venous plasma (0.100 mL) in a concentration range from the lower limit of quantification to 310 µg/L (capillary plasma) and 252 µg/L (venous plasma). The area under the plasma concentration versus time curve was similar in both matrices, while maximum concentrations were 37% higher in capillary plasma. In conclusion, capillary sampling should not bias pharmacokinetic exposure estimates compared with venous plasma values, if limited to sampling times in the distribution and elimination phases of finerenone.
描述了一种简单快速的高效液相色谱-串联质谱（HPLC-MS/MS）测定法，可灵敏且选择性地定量测定锂肝素人血浆中的非奈利酮（BAY 94-8862）。非奈利酮是一种新型选择性非甾体盐皮质激素受体拮抗剂，目前正在进行治疗慢性肾病的 III 期临床试验。非奈利酮的定量分析是在酸化乙腈沉淀蛋白后，加入其稳定同位素标记的内标（ISTD）进行的，然后通过 HPLC-MS/MS 分离和检测。该方法已对 0.100mL 血浆体积进行了验证，随后还对 0.010mL 的较低血浆体积进行了验证，例如在儿科研究中采集的体积。分析范围为 0.100µg/L（定量下限）至 200µg/L（定量上限）。对于 0.100mL 血浆体积，日间准确度为 99.7-105.0%，对于 0.010mL 血浆体积，日间准确度为 101.1-104.5%。日内精密度≤7.0%，与提取的血浆体积无关。观察到非奈利酮及其 ISTD 的离子化存在中等、浓度非依赖性基质效应，为 0.535-0.617，这可通过 ISTD 完全补偿（ISTD 归一化基质因子为 0.98-1.03）。该测定法已成功应用于两种经验证的血浆体积，用于一项临床 I 期研究，比较了 20mg 非奈利酮在毛细血管血浆（0.010mL）和静脉血浆（0.100mL）中的药代动力学，浓度范围从定量下限到 310µg/L（毛细血管血浆）和 252µg/L（静脉血浆）。两种基质中的血浆浓度-时间曲线下面积相似，而毛细血管血浆中的最大浓度高 37%。结论是，如果仅在非奈利酮分布和消除相的采样时间内进行，与静脉血浆值相比，毛细血管采样不应影响药代动力学暴露估计。
